Review
. 2022 Feb; 22(4):195-207.
doi: 10.1038/s41568-022-00442-9.

Mechanisms of immune activation and regulation: lessons from melanoma

Shelly Kalaora 1 Adi Nagler 1 Jennifer A Wargo 2 Yardena Samuels 3 
Affiliations
  • PMID: 35105962
  •     183 References

Abstract

Melanoma, a skin cancer that develops from pigment cells, has been studied intensively, particularly in terms of the immune response to tumours, and has been used as a model for the development of immunotherapy. This is due, in part, to the high mutational burden observed in melanomas, which increases both their immunogenicity and the infiltration of immune cells into the tumours, compared with other types of cancers. The immune response to melanomas involves a complex set of components and interactions. As the tumour evolves, it accumulates an increasing number of genetic and epigenetic alterations, some of which contribute to the immunogenicity of the tumour cells and the infiltration of immune cells. However, tumour evolution also enables the development of resistance mechanisms, which, in turn, lead to tumour immune escape. Understanding the interactions between melanoma tumour cells and the immune system, and the evolving changes within the melanoma tumour cells, the immune system and the microenvironment, is essential for the development of new cancer therapies. However, current research suggests that other extrinsic factors, such as the microbiome, may play a role in the immune response to melanomas. Here, we review the mechanisms underlying the immune response in the tumour and discuss recent advances as well as strategies for treatment development.

Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
Georgina V Long, Daniil Stroyakovskiy, +31 authors, Keith Flaherty.
Lancet, 2015 Jun 04; 386(9992). PMID: 26037941
Highly Cited.
Generation of specific anti-melanoma reactivity by stimulation of human tumor-infiltrating lymphocytes with MAGE-1 synthetic peptide.
M L Salgaller, J S Weber, +2 authors, S A Rosenberg.
Cancer Immunol Immunother, 1994 Aug 01; 39(2). PMID: 7519125
Advances in the development of personalized neoantigen-based therapeutic cancer vaccines.
Eryn Blass, Patrick A Ott.
Nat Rev Clin Oncol, 2021 Jan 22; 18(4). PMID: 33473220    Free PMC article.
Review.
Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study.
Margaret K Callahan, Harriet Kluger, +9 authors, Mario Sznol.
J Clin Oncol, 2017 Oct 19; 36(4). PMID: 29040030    Free PMC article.
Highly Cited.
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment.
Thomas F Gajewski.
Clin Cancer Res, 2007 Sep 19; 13(18 Pt 1). PMID: 17875753
Review.
The paradox of T-cell-mediated antitumor immunity in spite of poor clinical outcome in human melanoma.
Andrea Anichini, Claudia Vegetti, Roberta Mortarini.
Cancer Immunol Immunother, 2004 Jun 04; 53(10). PMID: 15175905
Review.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2015 Jun 02; 373(1). PMID: 26027431    Free PMC article.
Highly Cited.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Caroline Robert, Jacob Schachter, +20 authors, KEYNOTE-006 investigators.
N Engl J Med, 2015 Apr 22; 372(26). PMID: 25891173
Highly Cited.
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
Jedd D Wolchok, Vanna Chiarion-Sileni, +30 authors, James Larkin.
N Engl J Med, 2017 Sep 12; 377(14). PMID: 28889792    Free PMC article.
Highly Cited.
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2019 Sep 29; 381(16). PMID: 31562797
Highly Cited.
'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations.
Eric Tran, Paul F Robbins, Steven A Rosenberg.
Nat Immunol, 2017 Feb 16; 18(3). PMID: 28198830    Free PMC article.
Highly Cited. Review.
Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire.
Sebastian P Haen, Markus W Löffler, Hans-Georg Rammensee, Peter Brossart.
Nat Rev Clin Oncol, 2020 Jun 24; 17(10). PMID: 32572208    Free PMC article.
Review.
Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression.
Yong-Chen Lu, Xin Yao, +8 authors, Paul F Robbins.
J Immunol, 2013 May 22; 190(12). PMID: 23690473    Free PMC article.
Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma.
Shelly Kalaora, Yochai Wolf, +30 authors, Yardena Samuels.
Cancer Discov, 2018 Sep 14; 8(11). PMID: 30209080    Free PMC article.
Mutational heterogeneity in cancer and the search for new cancer-associated genes.
Michael S Lawrence, Petar Stojanov, +61 authors, Gad Getz.
Nature, 2013 Jun 19; 499(7457). PMID: 23770567    Free PMC article.
Highly Cited.
Neoantigens in cancer immunotherapy.
Ton N Schumacher, Robert D Schreiber.
Science, 2015 Apr 04; 348(6230). PMID: 25838375
Highly Cited. Review.
Developing neoantigen-targeted T cell-based treatments for solid tumors.
Tori N Yamamoto, Rigel J Kishton, Nicholas P Restifo.
Nat Med, 2019 Oct 09; 25(10). PMID: 31591590
Highly Cited. Review.
UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.
Yochai Wolf, Osnat Bartok, +26 authors, Yardena Samuels.
Cell, 2019 Sep 17; 179(1). PMID: 31522890    Free PMC article.
Highly Cited.
Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma.
Alexandre Reuben, Christine N Spencer, +51 authors, Jennifer A Wargo.
NPJ Genom Med, 2017 Aug 19; 2. PMID: 28819565    Free PMC article.
Highly Cited.
Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients.
Zhen Lin, Xianyi Meng, +6 authors, Aline Bozec.
Front Oncol, 2020 Dec 22; 10. PMID: 33344244    Free PMC article.
Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells.
Jason B Williams, Shuyin Li, +4 authors, Thomas F Gajewski.
Nat Commun, 2020 Feb 01; 11(1). PMID: 32001684    Free PMC article.
A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes.
Francesca Schiavetti, Joëlle Thonnard, +2 authors, Pierre G Coulie.
Cancer Res, 2002 Oct 03; 62(19). PMID: 12359761
Identification of bacteria-derived HLA-bound peptides in melanoma.
Shelly Kalaora, Adi Nagler, +50 authors, Yardena Samuels.
Nature, 2021 Mar 19; 592(7852). PMID: 33731925
The IFN gamma receptor: a paradigm for cytokine receptor signaling.
E A Bach, M Aguet, R D Schreiber.
Annu Rev Immunol, 1997 Jan 01; 15. PMID: 9143700
Highly Cited. Review.
Quantitative studies on viral interference in suspended L cells. III. Effect of interfering viruses and interferon on the growth rate of cells.
K PAUCKER, K CANTELL, W HENLE.
Virology, 1962 Jun 01; 17. PMID: 14484446
Highly Cited.
Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions.
Antje Sucker, Fang Zhao, +20 authors, Annette Paschen.
Nat Commun, 2017 Jun 01; 8. PMID: 28561041    Free PMC article.
Highly Cited.
Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3.
K E Cole, C A Strick, +9 authors, K Neote.
J Exp Med, 1998 Jun 24; 187(12). PMID: 9625760    Free PMC article.
Highly Cited.
A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines.
J M Farber.
Proc Natl Acad Sci U S A, 1990 Jul 01; 87(14). PMID: 2115167    Free PMC article.
Highly Cited.
Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins.
A D Luster, J C Unkeless, J V Ravetch.
Nature, 1985 Jun 20; 315(6021). PMID: 3925348
Highly Cited.
Recombinant interferon-gamma increases HLA-DR synthesis and expression.
T Y Basham, T C Merigan.
J Immunol, 1983 Apr 01; 130(4). PMID: 6403609
Highly Cited.
Induction of Ia and H-2 antigens on a macrophage cell line by immune interferon.
D P King, P P Jones.
J Immunol, 1983 Jul 01; 131(1). PMID: 6408177
Highly Cited.
Immunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma.
Shelly Kalaora, Joo Sang Lee, +15 authors, Yardena Samuels.
Nat Commun, 2020 Feb 16; 11(1). PMID: 32060274    Free PMC article.
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.
Joseph L Benci, Bihui Xu, +16 authors, Andy J Minn.
Cell, 2016 Dec 03; 167(6). PMID: 27912061    Free PMC article.
Highly Cited.
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
Jesse M Zaretsky, Angel Garcia-Diaz, +26 authors, Antoni Ribas.
N Engl J Med, 2016 Jul 20; 375(9). PMID: 27433843    Free PMC article.
Highly Cited.
In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.
Robert T Manguso, Hans W Pope, +16 authors, W Nicholas Haining.
Nature, 2017 Jul 21; 547(7664). PMID: 28723893    Free PMC article.
Highly Cited.
Some additional observations on the chemical nature of neutramycin.
M P Kunstmann, L A Mitscher.
Experientia, 1965 Jul 15; 21(7). PMID: 5870757
A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing.
Deng Pan, Aya Kobayashi, +13 authors, Kai W Wucherpfennig.
Science, 2018 Jan 06; 359(6377). PMID: 29301958    Free PMC article.
Highly Cited.
Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression.
C M D'Urso, Z G Wang, +3 authors, S Ferrone.
J Clin Invest, 1991 Jan 01; 87(1). PMID: 1898655    Free PMC article.
Highly Cited.
Genetic evolution of T-cell resistance in the course of melanoma progression.
Antje Sucker, Fang Zhao, +16 authors, Annette Paschen.
Clin Cancer Res, 2014 Oct 09; 20(24). PMID: 25294904    Free PMC article.
Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy.
N P Restifo, F M Marincola, +3 authors, S A Rosenberg.
J Natl Cancer Inst, 1996 Jan 17; 88(2). PMID: 8537970    Free PMC article.
Highly Cited.
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.
Ugur Sahin, Evelyna Derhovanessian, +47 authors, Özlem Türeci.
Nature, 2017 Jul 06; 547(7662). PMID: 28678784
Highly Cited.
Resistance to checkpoint blockade therapy through inactivation of antigen presentation.
Moshe Sade-Feldman, Yunxin J Jiao, +28 authors, Nir Hacohen.
Nat Commun, 2017 Oct 27; 8(1). PMID: 29070816    Free PMC article.
Highly Cited.
The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression.
Lu Huang, Shruti Malu, +23 authors, Patrick Hwu.
Clin Cancer Res, 2018 Mar 03; 24(14). PMID: 29496759
MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma.
Scott J Rodig, Daniel Gusenleitner, +13 authors, F Stephen Hodi.
Sci Transl Med, 2018 Jul 20; 10(450). PMID: 30021886
Highly Cited.
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
Douglas B Johnson, Monica V Estrada, +18 authors, Justin M Balko.
Nat Commun, 2016 Jan 30; 7. PMID: 26822383    Free PMC article.
Highly Cited.
Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity.
Marco Donia, Rikke Andersen, +6 authors, Inge Marie Svane.
Cancer Res, 2015 Jul 18; 75(18). PMID: 26183926
An immunogenic personal neoantigen vaccine for patients with melanoma.
Patrick A Ott, Zhuting Hu, +37 authors, Catherine J Wu.
Nature, 2017 Jul 06; 547(7662). PMID: 28678778    Free PMC article.
Highly Cited.
Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.
Zhuting Hu, Donna E Leet, +38 authors, Patrick A Ott.
Nat Med, 2021 Jan 23; 27(3). PMID: 33479501    Free PMC article.
Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.
Andrea Boni, Alexandria P Cogdill, +9 authors, Jennifer A Wargo.
Cancer Res, 2010 Jun 17; 70(13). PMID: 20551059
Highly Cited.
BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma.
Dennie T Frederick, Adriano Piris, +18 authors, Jennifer A Wargo.
Clin Cancer Res, 2013 Jan 12; 19(5). PMID: 23307859    Free PMC article.
Highly Cited.
Vemurafenib enhances MHC induction in BRAFV600E homozygous melanoma cells.
Bishu Sapkota, Charles E Hill, Brian P Pollack.
Oncoimmunology, 2013 Mar 14; 2(1). PMID: 23483066    Free PMC article.
Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest.
Nicolas Acquavella, David Clever, +24 authors, Nicholas P Restifo.
Cancer Immunol Res, 2014 Nov 02; 3(1). PMID: 25358764    Free PMC article.
The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells.
Hidetoshi Sumimoto, Fumie Imabayashi, Tomoko Iwata, Yutaka Kawakami.
J Exp Med, 2006 Jun 28; 203(7). PMID: 16801397    Free PMC article.
Highly Cited.
Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
Weiyi Peng, Jie Qing Chen, +41 authors, Patrick Hwu.
Cancer Discov, 2015 Dec 10; 6(2). PMID: 26645196    Free PMC article.
Highly Cited.
Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells.
Tomonori Yaguchi, Yasufumi Goto, +7 authors, Yutaka Kawakami.
J Immunol, 2012 Jul 21; 189(5). PMID: 22815287
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
Stefani Spranger, Riyue Bao, Thomas F Gajewski.
Nature, 2015 May 15; 523(7559). PMID: 25970248
Highly Cited.
Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy.
Stefani Spranger, Daisy Dai, Brendan Horton, Thomas F Gajewski.
Cancer Cell, 2017 May 10; 31(5). PMID: 28486109    Free PMC article.
Highly Cited.
ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment.
Chi-Fen Chen, Rolando Ruiz-Vega, +9 authors, Anand K Ganesan.
Cell Rep, 2017 Mar 09; 18(10). PMID: 28273450    Free PMC article.
Relationship between bodyweight and chemical composition of pigs at birth.
S E Curtis, C J Heidenreich, T G Martin.
J Anim Sci, 1967 Jul 01; 26(4). PMID: 6076867
Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition.
Jenny H Lee, Elena Shklovskaya, +15 authors, Helen Rizos.
Nat Commun, 2020 Apr 22; 11(1). PMID: 32312968    Free PMC article.
Tumor-infiltrating lymphocytes in the immunotherapy era.
Sterre T Paijens, Annegé Vledder, Marco de Bruyn, Hans W Nijman.
Cell Mol Immunol, 2020 Nov 04; 18(4). PMID: 33139907    Free PMC article.
Review.
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
Itay Tirosh, Benjamin Izar, +34 authors, Levi A Garraway.
Science, 2016 Apr 29; 352(6282). PMID: 27124452    Free PMC article.
Highly Cited.
A guide to cancer immunotherapy: from T cell basic science to clinical practice.
Alex D Waldman, Jill M Fritz, Michael J Lenardo.
Nat Rev Immunol, 2020 May 21; 20(11). PMID: 32433532    Free PMC article.
Review.
Foreperiod effect on time estimation and simple reaction time in schizophrenia.
S M Suchoon, R Kersey.
J Clin Psychol, 1980 Jan 01; 36(1). PMID: 7391259
Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy.
Riyao Yang, Linlin Sun, +14 authors, Mien-Chie Hung.
Nat Commun, 2021 Feb 07; 12(1). PMID: 33547304    Free PMC article.
TIM3 comes of age as an inhibitory receptor.
Yochai Wolf, Ana C Anderson, Vijay K Kuchroo.
Nat Rev Immunol, 2019 Nov 05; 20(3). PMID: 31676858    Free PMC article.
Review.
Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma.
Moshe Sade-Feldman, Keren Yizhak, +32 authors, Nir Hacohen.
Cell, 2019 Jan 12; 176(1-2). PMID: 30633907    Free PMC article.
Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade.
Ines Pires da Silva, Anne Gallois, +5 authors, Nina Bhardwaj.
Cancer Immunol Res, 2014 May 06; 2(5). PMID: 24795354    Free PMC article.
Highly Cited.
CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.
Julien Fourcade, Zhaojun Sun, +7 authors, Hassane M Zarour.
Cancer Res, 2011 Dec 30; 72(4). PMID: 22205715    Free PMC article.
Highly Cited.
Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4.
Shuang Qin, Linping Xu, +3 authors, Suxia Luo.
Mol Cancer, 2019 Nov 07; 18(1). PMID: 31690319    Free PMC article.
Highly Cited. Review.
B7-h4 expression in human melanoma: its association with patients' survival and antitumor immune response.
Dagmar Quandt, Eckhard Fiedler, +2 authors, Barbara Seliger.
Clin Cancer Res, 2011 Mar 08; 17(10). PMID: 21378130
VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival.
Lawrence F Kuklinski, Shaofeng Yan, +6 authors, Marc S Ernstoff.
Cancer Immunol Immunother, 2018 May 09; 67(7). PMID: 29737375
Targeting Adenosine in BRAF-Mutant Melanoma Reduces Tumor Growth and Metastasis.
Arabella Young, Shin Foong Ngiow, +14 authors, Mark J Smyth.
Cancer Res, 2017 Jun 28; 77(17). PMID: 28652244
Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function.
Young-Hee Lee, Natalia Martin-Orozco, +23 authors, Chen Dong.
Cell Res, 2017 Jul 08; 27(8). PMID: 28685773    Free PMC article.
Highly Cited.
In vivo discovery of immunotherapy targets in the tumour microenvironment.
Penghui Zhou, Donald R Shaffer, +17 authors, Kai W Wucherpfennig.
Nature, 2014 Jan 31; 506(7486). PMID: 24476824    Free PMC article.
Highly Cited.
Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function.
Eric Shifrut, Julia Carnevale, +7 authors, Alexander Marson.
Cell, 2018 Nov 20; 175(7). PMID: 30449619    Free PMC article.
Highly Cited.
Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
Rita Cabrita, Martin Lauss, +22 authors, Göran Jönsson.
Nature, 2020 Jan 17; 577(7791). PMID: 31942071
Highly Cited.
B cells and tertiary lymphoid structures promote immunotherapy response.
Beth A Helmink, Sangeetha M Reddy, +57 authors, Jennifer A Wargo.
Nature, 2020 Jan 17; 577(7791). PMID: 31942075    Free PMC article.
Highly Cited.
Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.
Lucas Ferrari de Andrade, Rong En Tay, +14 authors, Kai W Wucherpfennig.
Science, 2018 Mar 31; 359(6383). PMID: 29599246    Free PMC article.
Highly Cited.
Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin.
Weifeng He, Jianlei Hao, +12 authors, Zhinan Yin.
J Immunol, 2010 Jun 08; 185(1). PMID: 20525896    Free PMC article.
Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial.
Mark A Exley, Phillip Friedlander, +15 authors, Steven P Balk.
Clin Cancer Res, 2017 Feb 15; 23(14). PMID: 28193627    Free PMC article.
Highly Cited.
MAIT cells regulate NK cell-mediated tumor immunity.
Emma V Petley, Hui-Fern Koay, +28 authors, Phillip K Darcy.
Nat Commun, 2021 Aug 08; 12(1). PMID: 34362900    Free PMC article.
MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1.
Juming Yan, Stacey Allen, +10 authors, Michele W L Teng.
Cancer Discov, 2019 Dec 13; 10(1). PMID: 31826876
Utility of tumour-infiltrating CD25+FOXP3+ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma.
Clelia Miracco, Vasileios Mourmouras, +6 authors, Pietro Luzi.
Oncol Rep, 2007 Oct 05; 18(5). PMID: 17914561
Circulating CD4+ CD25(high) CD127(low) regulatory T cells are an independent predictor of advanced melanoma.
T Gambichler, M Bindsteiner, +2 authors, A Kreuter.
Pigment Cell Melanoma Res, 2012 Dec 05; 26(2). PMID: 23205892
GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment.
Marie Jo Halaby, Kebria Hezaveh, +16 authors, Tracy L McGaha.
Sci Immunol, 2019 Dec 15; 4(42). PMID: 31836669    Free PMC article.
Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion.
Linda Ziani, Thouraya Ben Safta-Saadoun, +5 authors, Jerome Thiery.
Oncotarget, 2017 Apr 21; 8(12). PMID: 28423623    Free PMC article.
Mechanical forces in the immune system.
Morgan Huse.
Nat Rev Immunol, 2017 Aug 02; 17(11). PMID: 28757604    Free PMC article.
Highly Cited. Review.
Concepts of extracellular matrix remodelling in tumour progression and metastasis.
Juliane Winkler, Abisola Abisoye-Ogunniyan, Kevin J Metcalf, Zena Werb.
Nat Commun, 2020 Oct 11; 11(1). PMID: 33037194    Free PMC article.
Review.
Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility.
Amanpreet Kaur, Brett L Ecker, +27 authors, Ashani T Weeraratna.
Cancer Discov, 2018 Oct 04; 9(1). PMID: 30279173    Free PMC article.
Highly Cited.
Phagocytosis checkpoints as new targets for cancer immunotherapy.
Mingye Feng, Wen Jiang, +3 authors, Irving L Weissman.
Nat Rev Cancer, 2019 Aug 30; 19(10). PMID: 31462760    Free PMC article.
Highly Cited. Review.
Posttranscriptional control of T cell effector function by aerobic glycolysis.
Chih-Hao Chang, Jonathan D Curtis, +11 authors, Erika L Pearce.
Cell, 2013 Jun 12; 153(6). PMID: 23746840    Free PMC article.
Highly Cited.
Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy.
Mahima Swamy, Shalini Pathak, +4 authors, Doreen A Cantrell.
Nat Immunol, 2016 Apr 26; 17(6). PMID: 27111141    Free PMC article.
Highly Cited.
Inhibition of T cell proliferation by macrophage tryptophan catabolism.
D H Munn, E Shafizadeh, +3 authors, A L Mellor.
J Exp Med, 1999 May 04; 189(9). PMID: 10224276    Free PMC article.
Highly Cited.
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.
David H Munn, Madhav D Sharma, +4 authors, Andrew L Mellor.
Immunity, 2005 May 17; 22(5). PMID: 15894280
Highly Cited.
Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response.
Mark S Sundrud, Sergei B Koralov, +10 authors, Anjana Rao.
Science, 2009 Jun 06; 324(5932). PMID: 19498172    Free PMC article.
Highly Cited.
Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells.
Zaheed Husain, Yannu Huang, Pankaj Seth, Vikas P Sukhatme.
J Immunol, 2013 Jul 03; 191(3). PMID: 23817426
Highly Cited.
LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.
Almut Brand, Katrin Singer, +36 authors, Marina Kreutz.
Cell Metab, 2016 Sep 20; 24(5). PMID: 27641098
Highly Cited.
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.
Chih-Hao Chang, Jing Qiu, +11 authors, Erika L Pearce.
Cell, 2015 Sep 01; 162(6). PMID: 26321679    Free PMC article.
Highly Cited.
The Life History of a Micro-Parasite Isolated from Carcinomatous Growths.
E W Stearn, B F Sturdivant, A E Stearn.
Proc Natl Acad Sci U S A, 1925 Oct 01; 11(10). PMID: 16587062    Free PMC article.
The cost of complying with OSHA's bloodborne pathogens regulations.
N E Cahill.
Am J Health Syst Pharm, 1995 Feb 15; 52(4). PMID: 7757858
The microbiome and cancer.
Robert F Schwabe, Christian Jobin.
Nat Rev Cancer, 2013 Oct 18; 13(11). PMID: 24132111    Free PMC article.
Highly Cited. Review.
Association of Dietary Patterns With Risk of Colorectal Cancer Subtypes Classified by Fusobacterium nucleatum in Tumor Tissue.
Raaj S Mehta, Reiko Nishihara, +21 authors, Shuji Ogino.
JAMA Oncol, 2017 Jan 27; 3(7). PMID: 28125762    Free PMC article.
Highly Cited.
Cancer and the microbiota.
Wendy S Garrett.
Science, 2015 Apr 04; 348(6230). PMID: 25838377    Free PMC article.
Highly Cited. Review.
The effect of succinylcholine on deneravated fast and slow skeletal muscle.
B Salafsky.
Arch Int Pharmacodyn Ther, 1968 Aug 01; 174(2). PMID: 5727343
Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy.
TaChung Yu, Fangfang Guo, +12 authors, Jing-Yuan Fang.
Cell, 2017 Jul 29; 170(3). PMID: 28753429    Free PMC article.
Highly Cited.
Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab.
N Chaput, P Lepage, +15 authors, F Carbonnel.
Ann Oncol, 2019 Aug 14; 30(12). PMID: 31408090
Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients.
Arthur E Frankel, Laura A Coughlin, +4 authors, Andrew Y Koh.
Neoplasia, 2017 Sep 20; 19(10). PMID: 28923537    Free PMC article.
Highly Cited.
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.
V Gopalakrishnan, C N Spencer, +67 authors, J A Wargo.
Science, 2017 Nov 04; 359(6371). PMID: 29097493    Free PMC article.
Highly Cited.
The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.
Vyara Matson, Jessica Fessler, +5 authors, Thomas F Gajewski.
Science, 2018 Jan 06; 359(6371). PMID: 29302014    Free PMC article.
Highly Cited.
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
Bertrand Routy, Emmanuelle Le Chatelier, +45 authors, Laurence Zitvogel.
Science, 2017 Nov 04; 359(6371). PMID: 29097494
Highly Cited.
Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.
Ayelet Sivan, Leticia Corrales, +9 authors, Thomas F Gajewski.
Science, 2015 Nov 07; 350(6264). PMID: 26541606    Free PMC article.
Highly Cited.
Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.
Marie Vétizou, Jonathan M Pitt, +35 authors, Laurence Zitvogel.
Science, 2015 Nov 07; 350(6264). PMID: 26541610    Free PMC article.
Highly Cited.
Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.
Erez N Baruch, Ilan Youngster, +29 authors, Ben Boursi.
Science, 2020 Dec 12; 371(6529). PMID: 33303685
Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.
Diwakar Davar, Amiran K Dzutsev, +29 authors, Hassane M Zarour.
Science, 2021 Feb 06; 371(6529). PMID: 33542131    Free PMC article.
A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.
Takeshi Tanoue, Satoru Morita, +25 authors, Kenya Honda.
Nature, 2019 Jan 25; 565(7741). PMID: 30675064
Highly Cited.
Microbiome analyses of blood and tissues suggest cancer diagnostic approach.
Gregory D Poore, Evguenia Kopylova, +14 authors, Rob Knight.
Nature, 2020 Mar 28; 579(7800). PMID: 32214244    Free PMC article.
Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma.
Gongjian Zhu, Haixiang Su, +3 authors, Lingeng Lu.
Eur J Cancer, 2021 May 08; 151. PMID: 33962358    Free PMC article.
The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.
Smruti Pushalkar, Mautin Hundeyin, +30 authors, George Miller.
Cancer Discov, 2018 Mar 24; 8(4). PMID: 29567829    Free PMC article.
Highly Cited.
Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.
Chamutal Gur, Yara Ibrahim, +21 authors, Ofer Mandelboim.
Immunity, 2015 Feb 15; 42(2). PMID: 25680274    Free PMC article.
Highly Cited.
Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status.
Tsuyoshi Hamada, Xuehong Zhang, +29 authors, Shuji Ogino.
Cancer Immunol Res, 2018 Sep 20; 6(11). PMID: 30228205    Free PMC article.
Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study.
Nancy E Thomas, Klaus J Busam, +20 authors, Marianne Berwick.
J Clin Oncol, 2013 Oct 16; 31(33). PMID: 24127443    Free PMC article.
Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
Pei-Ling Chen, Whijae Roh, +41 authors, Jennifer A Wargo.
Cancer Discov, 2016 Jun 16; 6(8). PMID: 27301722    Free PMC article.
Highly Cited.
PD-1 blockade induces responses by inhibiting adaptive immune resistance.
Paul C Tumeh, Christina L Harview, +23 authors, Antoni Ribas.
Nature, 2014 Nov 28; 515(7528). PMID: 25428505    Free PMC article.
Highly Cited.
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
Nadeem Riaz, Jonathan J Havel, +22 authors, Timothy A Chan.
Cell, 2017 Oct 17; 171(4). PMID: 29033130    Free PMC article.
Highly Cited.
Molecular and genetic properties of tumors associated with local immune cytolytic activity.
Michael S Rooney, Sachet A Shukla, +2 authors, Nir Hacohen.
Cell, 2015 Jan 17; 160(1-2). PMID: 25594174    Free PMC article.
Highly Cited.
[Acetylcholine potentiation of the serotonin-induced contractile reaction of the cat pyloric sphincter].
T P Ses', V I Ovsiannikov.
Fiziol Zh SSSR Im I M Sechenova, 1983 Oct 01; 69(10). PMID: 6641984
Clonal replacement of tumor-specific T cells following PD-1 blockade.
Kathryn E Yost, Ansuman T Satpathy, +13 authors, Howard Y Chang.
Nat Med, 2019 Jul 31; 25(8). PMID: 31359002    Free PMC article.
Highly Cited.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127    Free PMC article.
Highly Cited.
Nivolumab plus ipilimumab in advanced melanoma.
Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867    Free PMC article.
Highly Cited.
Nivolumab in previously untreated melanoma without BRAF mutation.
Caroline Robert, Georgina V Long, +25 authors, Paolo A Ascierto.
N Engl J Med, 2014 Nov 18; 372(4). PMID: 25399552
Highly Cited.
Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma.
Catherine S Grasso, Jennifer Tsoi, +33 authors, Antoni Ribas.
Cancer Cell, 2020 Sep 12; 38(4). PMID: 32916126    Free PMC article.
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
Alexandra Snyder, Vladimir Makarov, +18 authors, Timothy A Chan.
N Engl J Med, 2014 Nov 20; 371(23). PMID: 25409260    Free PMC article.
Highly Cited.
Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma.
Stefani Spranger, Jason J Luke, +6 authors, Thomas F Gajewski.
Proc Natl Acad Sci U S A, 2016 Nov 12; 113(48). PMID: 27837020    Free PMC article.
Highly Cited.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
Willy Hugo, Jesse M Zaretsky, +15 authors, Roger S Lo.
Cell, 2016 Mar 22; 165(1). PMID: 26997480    Free PMC article.
Highly Cited.
Publisher Correction: Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.
Antoni Ribas, Donald Lawrence, +14 authors, Omid Hamid.
Nat Med, 2019 Jul 04; 25(8). PMID: 31267021
Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma.
Paolo Antonio Ascierto, Pier Francesco Ferrucci, +16 authors, Antoni Ribas.
Nat Med, 2019 Jun 07; 25(6). PMID: 31171878
Highly Cited.
Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.
Ryan J Sullivan, Omid Hamid, +13 authors, Patrick Hwu.
Nat Med, 2019 Jun 07; 25(6). PMID: 31171876
Highly Cited.
Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy.
Antoni Ribas, Reinhard Dummer, +17 authors, Georgina V Long.
Cell, 2017 Sep 09; 170(6). PMID: 28886381    Free PMC article.
Highly Cited.
Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain.
Manisha Singh, Christina Vianden, +15 authors, Willem W Overwijk.
Nat Commun, 2017 Nov 14; 8(1). PMID: 29129918    Free PMC article.
An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.
Ugur Sahin, Petra Oehm, +38 authors, Özlem Türeci.
Nature, 2020 Jul 31; 585(7823). PMID: 32728218
Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.
Lionel Apetoh, François Ghiringhelli, +25 authors, Laurence Zitvogel.
Nat Med, 2007 Aug 21; 13(9). PMID: 17704786
Highly Cited.
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
Christina Twyman-Saint Victor, Andrew J Rech, +22 authors, Andy J Minn.
Nature, 2015 Mar 11; 520(7547). PMID: 25754329    Free PMC article.
Highly Cited.
Cancer regression in patients after transfer of genetically engineered lymphocytes.
Richard A Morgan, Mark E Dudley, +13 authors, Steven A Rosenberg.
Science, 2006 Sep 02; 314(5796). PMID: 16946036    Free PMC article.
Highly Cited.
CRISPR-engineered T cells in patients with refractory cancer.
Edward A Stadtmauer, Joseph A Fraietta, +38 authors, Carl H June.
Science, 2020 Feb 08; 367(6481). PMID: 32029687
Highly Cited.
Modulating gut microbes.
Jennifer A Wargo.
Science, 2020 Sep 12; 369(6509). PMID: 32913089
Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.
Helena Harlin, Yuru Meng, +5 authors, Thomas F Gajewski.
Cancer Res, 2009 Mar 19; 69(7). PMID: 19293190    Free PMC article.
Highly Cited.
IL-2: the first effective immunotherapy for human cancer.
Steven A Rosenberg.
J Immunol, 2014 Jun 08; 192(12). PMID: 24907378    Free PMC article.
Highly Cited. Review.
Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial.
Shihong Zhang, Karan Kohli, +11 authors, Seth M Pollack.
Cancer Immunol Res, 2019 Jun 07; 7(8). PMID: 31171504    Free PMC article.
A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control.
Zhichen Sun, Zhenhua Ren, +12 authors, Hua Peng.
Nat Commun, 2019 Aug 30; 10(1). PMID: 31462678    Free PMC article.
SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study.
Antoni Ribas, Theresa Medina, +11 authors, Robert S Janssen.
Cancer Discov, 2018 Aug 30; 8(10). PMID: 30154193    Free PMC article.
Highly Cited.
Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells.
Pascale André, Caroline Denis, +27 authors, Eric Vivier.
Cell, 2018 Dec 07; 175(7). PMID: 30503213    Free PMC article.
Highly Cited. Review.
Unconventional T Cell Targets for Cancer Immunotherapy.
Dale I Godfrey, Jérôme Le Nours, +2 authors, Jamie Rossjohn.
Immunity, 2018 Mar 22; 48(3). PMID: 29562195
Highly Cited. Review.
Prospects for gene-engineered T cell immunotherapy for solid cancers.
Christopher A Klebanoff, Steven A Rosenberg, Nicholas P Restifo.
Nat Med, 2016 Jan 07; 22(1). PMID: 26735408    Free PMC article.
Highly Cited.
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.
Enli Liu, David Marin, +24 authors, Katayoun Rezvani.
N Engl J Med, 2020 Feb 06; 382(6). PMID: 32023374    Free PMC article.
Highly Cited.
Human chimeric antigen receptor macrophages for cancer immunotherapy.
Michael Klichinsky, Marco Ruella, +23 authors, Saar Gill.
Nat Biotechnol, 2020 May 04; 38(8). PMID: 32361713    Free PMC article.
Engineering advanced logic and distributed computing in human CAR immune cells.
Jang Hwan Cho, Atsushi Okuma, +3 authors, Wilson W Wong.
Nat Commun, 2021 Feb 06; 12(1). PMID: 33542232    Free PMC article.
Use of HLA peptidomics and whole exome sequencing to identify human immunogenic neo-antigens.
Shelly Kalaora, Eilon Barnea, +8 authors, Yardena Samuels.
Oncotarget, 2016 Jan 29; 7(5). PMID: 26819371    Free PMC article.
Highly Cited.
Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry.
Michal Bassani-Sternberg, Eva Bräunlein, +16 authors, Angela M Krackhardt.
Nat Commun, 2016 Nov 22; 7. PMID: 27869121    Free PMC article.
Highly Cited.
Exploration of peptides bound to MHC class I molecules in melanoma.
Antonia L Pritchard, Marcus L Hastie, +3 authors, Nicholas K Hayward.
Pigment Cell Melanoma Res, 2015 Feb 04; 28(3). PMID: 25645385
Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells.
Paul F Robbins, Yong-Chen Lu, +9 authors, Steven A Rosenberg.
Nat Med, 2013 May 07; 19(6). PMID: 23644516    Free PMC article.
Highly Cited.
Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients.
Alena Gros, Maria R Parkhurst, +11 authors, Steven A Rosenberg.
Nat Med, 2016 Feb 24; 22(4). PMID: 26901407    Free PMC article.
Highly Cited.
Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens.
Todd D Prickett, Jessica S Crystal, +11 authors, Paul F Robbins.
Cancer Immunol Res, 2016 Jun 18; 4(8). PMID: 27312342    Free PMC article.
The response of autologous T cells to a human melanoma is dominated by mutated neoantigens.
Volker Lennerz, Martina Fatho, +6 authors, Thomas Wölfel.
Proc Natl Acad Sci U S A, 2005 Oct 26; 102(44). PMID: 16247014    Free PMC article.
Highly Cited.
High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma.
Carsten Linnemann, Marit M van Buuren, +13 authors, Ton N M Schumacher.
Nat Med, 2014 Dec 23; 21(1). PMID: 25531942
Highly Cited.
Dissection of T-cell antigen specificity in human melanoma.
Rikke Sick Andersen, Charlotte Albæk Thrue, +7 authors, Sine Reker Hadrup.
Cancer Res, 2012 Feb 09; 72(7). PMID: 22311675
TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients.
Pia Kvistborg, Chengyi Jenny Shu, +19 authors, Ton N M Schumacher.
Oncoimmunology, 2012 Jul 04; 1(4). PMID: 22754759    Free PMC article.
Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes.
Cyrille J Cohen, Jared J Gartner, +11 authors, Paul F Robbins.
J Clin Invest, 2015 Sep 22; 125(10). PMID: 26389673    Free PMC article.
Highly Cited.
Ribosomal Database Project: data and tools for high throughput rRNA analysis.
James R Cole, Qiong Wang, +7 authors, James M Tiedje.
Nucleic Acids Res, 2013 Nov 30; 42(Database issue). PMID: 24288368    Free PMC article.
Highly Cited.
Use of Metatranscriptomics in Microbiome Research.
Stavros Bashiardes, Gili Zilberman-Schapira, Eran Elinav.
Bioinform Biol Insights, 2016 Apr 30; 10. PMID: 27127406    Free PMC article.
Highly Cited. Review.
Ongoing revolution in bacteriology: routine identification of bacteria by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
Piseth Seng, Michel Drancourt, +4 authors, Didier Raoult.
Clin Infect Dis, 2009 Jul 09; 49(4). PMID: 19583519
Highly Cited.
Matrix-assisted laser desorption ionization-time of flight mass spectrometry: a fundamental shift in the routine practice of clinical microbiology.
Andrew E Clark, Erin J Kaleta, Amit Arora, Donna M Wolk.
Clin Microbiol Rev, 2013 Jul 05; 26(3). PMID: 23824373    Free PMC article.
Highly Cited. Review.