Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

Abstract

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

Image-based assessment of extracellular mucin-to-tumor area predicts consensus molecular subtypes (CMS) in colorectal cancer

“…First, MSI status serves as a diagnostic tool to help identify colorectal cancers arising from a possible familial setting (e.g. Lynch syndrome) 2 . Second, in general, patients with stage II colorectal cancers seem to derive a survival benefit with MSI 3 .…”

Precision medicine for metastatic colorectal cancer in clinical practice

“…Therefore, current studies aim to identify predictive markers to improve patient stratification and to establish combination strategies for improving efficacy, especially in patients with pMMR tumors. Several studies are testing combination strategies of checkpoint inhibitors with chemotherapy, radiation, anti-VEGF antibodies, anti-EGFR antibodies, inhibitors of mitogen-activated protein kinase (MAPK) signaling, or multi-tyrosine kinase inhibitors aiming to turn immunologically ‘cold’ tumors into ‘hot’ tumors and thereby making them susceptible to immunotherapies (reviewed in Pecci et al 91 and Hirano et al, 80 Figure 1 ).…”

“…With respect to immunotherapy, the pathway has been implicated in tumor–immune interaction in multiple ways, including regulation of immunosuppression through cytokines and growth factors, regulation of human leukocyte antigen (HLA) expression and thereby immune cell evasion from the tumor microenvironment. 91 The combination of atezolizumab with MEK inhibition using cobimetinib, however, led to disappointing efficacy in the phase III IMblaze370 trial, analyzing 363 pretreated patients: the combination led to an OS of 8.9 months compared with 7.1 months for atezolizumab alone and 8.5 months with the control treatment regorafenib. 103 Clinical trials combining checkpoint inhibitors with EGFR antibodies cetuximab and panitumumab with and without chemotherapy are ongoing.…”

Non-Coding RNAs Regulate the Resistance to Anti-EGFR Therapy in Colorectal Cancer

“…MiR-148a-3p and miR-448 respectively down-regulate the expression of calnexin (CANX) and indoleamine 2,3-dioxygenase 1 (IDO1), which enhances CD8 + T cell-mediated immune response in CRC (67,68). Cetuximab can induce ADCC by binding to EGFR on cancer cells and CD16 receptor on natural killer (NK) cells and dendritic cells (DCs) (69)(70)(71). It stimulates the production of proinflammatory cytokines, such as IFN-g and TNF-a, and activates cytotoxic T cells in the TME, thereby exerting tumor immunosuppressive effects (69)(70)(71).…”

“…Cetuximab can induce ADCC by binding to EGFR on cancer cells and CD16 receptor on natural killer (NK) cells and dendritic cells (DCs) (69)(70)(71). It stimulates the production of proinflammatory cytokines, such as IFN-g and TNF-a, and activates cytotoxic T cells in the TME, thereby exerting tumor immunosuppressive effects (69)(70)(71). It has been suggested that anti-EGFR therapy and immunotherapy have synergetic and complementary mechanisms.…”