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

Abstract

Advanced 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.

Keywords: Colorectal cancer; Immune checkpoint inhibitors; Proficient DNA mismatch repair, Tumor microenvironment.

Fig. 1

pMMR CRC are characterized by an immune-excluded and immune-suppressive tumor microenvironment (TME), leading to resistance to immune checkpoint inhibitors (ICIs). In fact, tumor-infiltrating lymphocytes (TILs) and antigen-presenting cells (APCs) are located outside of tumor core and inner invasive margin, reducing their direct contact with tumor cells. Inside tumor core, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (Treg) lead to suppression of immune response against cancer cells. Moreover, pMMR CRC detains low levels of neoantigens, impairing their presentation to CD8+ T cells. In this immune-excluded and immune-suppressive TME, chemotherapy, inducing immunogenic cell death (ICD), promotes exposure on tumor cell surface of calreticulin, able to inhibit tumor angiogenesis and increased TILs inside TME, and of heat shock protein (HSP) 70 and 90, able to bind CD40 on dendritic cells (DCs) and activating them. Moreover, ICD promotes the release from tumor cells of HMGB1 that could bind TLR4 on DCs surface and promote their activation. Radiotherapy leads to increased neoantigen presentation and release from tumor cells and increased expression of PD-L1. Anti-angiogenesis drugs, such as bevacizumab, and other multikinase inhibitors (MKI), such as regorafenib, are able to inhibit the immuno-suppressive effect of VEGF/VEGFR on TME, blocking the infiltration of MDSCs, TAMs, and Treg inside TME and the expression of T cell exhaustion markers (PD-1, LAG3, TIM3). Anti-EGFR drugs, inducing antibody-dependent cell-mediated cytotoxicity (ADCC), lead to cancer cells lysis by natural killer (NK) cells. Finally, alterations of MAPK pathway on cancer cells promote migration of suppressive immune cells inside TME and reduce TILs infiltration; therefore, drugs that target this axis might restore antitumor immune cell activity.