Review
. 2021 Mar; 11:573547.
doi: 10.3389/fonc.2021.573547.

The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

Guanglin Cui 1 
Affiliations
  • PMID: 33763344
  •     116 References
  •     4 citations

Abstract

Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more "sensitive" in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

Keywords: colorectal cancer; immune checkpoint; inhibitor; metastasis; therapy.

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Cell Rep, 2016 May 07; 15(4). PMID: 27149842    Free PMC article.
Highly Cited.
Mechanisms of Resistance to Checkpoint Blockade Therapy.
Hubing Shi, Jiang Lan, Jiqiao Yang.
Adv Exp Med Biol, 2020 Mar 19; 1248. PMID: 32185708
Review.
A subset of patients with MSS/MSI-low-colorectal cancer showed increased CD8(+) TILs together with up-regulated IFN-γ.
Tomohiro Kikuchi, Kosaku Mimura, +12 authors, Koji Kono.
Oncol Lett, 2019 Dec 04; 18(6). PMID: 31788072    Free PMC article.
Immunopathologic Stratification of Colorectal Cancer for Checkpoint Blockade Immunotherapy.
Nicolas J Llosa, Brandon Luber, +15 authors, Robert A Anders.
Cancer Immunol Res, 2019 Aug 24; 7(10). PMID: 31439614    Free PMC article.
Immune battle at the premalignant stage of colorectal cancer: focus on immune cell compositions, functions and cytokine products.
Guanglin Cui.
Am J Cancer Res, 2020 Jun 09; 10(5). PMID: 32509381    Free PMC article.
Review.
Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape.
Takuro Noguchi, Jeffrey P Ward, +8 authors, Robert D Schreiber.
Cancer Immunol Res, 2017 Jan 12; 5(2). PMID: 28073774    Free PMC article.
Highly Cited.
Contribution of IL-33 to the Pathogenesis of Colorectal Cancer.
Guanglin Cui, Aping Yuan, +3 authors, Rasmus Goll.
Front Oncol, 2018 Dec 14; 8. PMID: 30547011    Free PMC article.
Review.
Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers.
Luisa Carbognin, Sara Pilotto, +11 authors, Giampaolo Tortora.
PLoS One, 2015 Jun 19; 10(6). PMID: 26086854    Free PMC article.
Highly Cited.
Immunomodulating antibodies in the treatment of metastatic melanoma: the experience with anti-CTLA-4, anti-CD137, and anti-PD1.
Ester Simeone, Paolo A Ascierto.
J Immunotoxicol, 2012 Apr 25; 9(3). PMID: 22524673
Review.
Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy.
Etienne Becht, Aurélien de Reyniès, +7 authors, Wolf Herman Fridman.
Clin Cancer Res, 2016 Mar 20; 22(16). PMID: 26994146
Highly Cited.
Tumor Infiltrating Lymphocytes and Macrophages Improve Survival in Microsatellite Unstable Colorectal Cancer.
Sumana Narayanan, Tsutomu Kawaguchi, +4 authors, Kazuaki Takabe.
Sci Rep, 2019 Sep 19; 9(1). PMID: 31530839    Free PMC article.
Highly Cited.
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
Julie R Brahmer, Charles G Drake, +17 authors, Suzanne L Topalian.
J Clin Oncol, 2010 Jun 03; 28(19). PMID: 20516446    Free PMC article.
Highly Cited.
The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy.
James W T Toh, Paul de Souza, +4 authors, Kevin J Spring.
Clin Colorectal Cancer, 2016 Aug 25; 15(4). PMID: 27553906
Review.
Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma.
Bert H O'Neil, John M Wallmark, +14 authors, Sae-Won Han.
PLoS One, 2017 Dec 29; 12(12). PMID: 29284010    Free PMC article.
Highly Cited.
Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors.
Inken Salewski, Julia Henne, +7 authors, Claudia Maletzki.
Int J Mol Sci, 2021 Jul 03; 22(11). PMID: 34206051    Free PMC article.
Durable complete response to pembrolizumab in microsatellite stable colorectal cancer.
Marzieh Gomar, Masoumeh Najafi, +2 authors, Amin Jahanbakhshi.
Daru, 2021 Jul 14; 29(2). PMID: 34254265    Free PMC article.
Clinical Study of Sintilimab as Second-Line or Above Therapy in Patients With Advanced or Metastatic Gastric Cancer: A Retrospective Study.
Caiyun Nie, Huifang Lv, +4 authors, Xiaobing Chen.
Front Oncol, 2021 Oct 12; 11. PMID: 34631579    Free PMC article.
Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival.
Peiyi Xie, Hong Zheng, +7 authors, Xiaochun Meng.
BMC Cancer, 2021 Nov 21; 21(1). PMID: 34798858    Free PMC article.