The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…This subgroup also exhibited a high expression of T-cell activation and chemotaxis markers, such as IFN-γ, IL-15, CXCL9, and CXCL10 as well as of PDCD1 [PD-1], CTLA-4, and LAG3. The MSI-enriched subgroup has the best prognosis (Budinska et al, 2013;De Sousa E Melo et al, 2013;Dienstmann et al, 2014;Marisa et al, 2013;Roepman et al, 2014;Sadanandam et al, 2013;Schlicker et al, 2012), is highly infiltrated with CD8 + T cells expressing PD-1 as an activation marker (Llosa et al, 2015), and encompasses the few CRC patients who responded to anti-PD-1 therapies (Le et al, 2015). Another molecularly defined subgroup also exhibited a strong immune signature.…”

Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

“…The lower response rate to PD-1 and PD-L1 blockade observed in CRC patients compared to lung, renal and melanoma, required a comprehensive analysis of the microenvironment of this cancer type [13]. Accordingly, Llosa et al [47] analyzed the immune microenvironment of a large series of primary CRC: a subset of CRC presented high infiltration with activated CD8+ CTL and Th1 cells, plus high levels of IFN-c production and Th1 transcription factor Tbet [47]; genetically, nearly all these tumors were characterized by defects in mismatch repair, though, the basis for the relationship between these two aspects was not completely understood [47]. An explanation may be that this dense immune infiltrate was directed to the high number of neo-antigens resulting from the huge mutational load, much higher than in the MSS tumors (typically 10-50 times) [47].…”

“…Further evidence on the link between the tumor genotype with the immune microenvironment and its potential implications emerged from studies on colorectal cancer (CRC) [47,79]. The lower response rate to PD-1 and PD-L1 blockade observed in CRC patients compared to lung, renal and melanoma, required a comprehensive analysis of the microenvironment of this cancer type [13].…”

“…There is a large body of evidence supporting that the tumor immune microenvironment is unique and complex, it may have a crucial role in promoting carcinogenesis and maintaining malignant cells growth [47][48][49]. The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been widely recognized [48,[50][51][52].…”

PD-1 and PD-L1 blockade in gastrointestinal malignancies

“…Correlative analysis suggests the mutational load in the tumours of MSI patients may be the mechanism through which the PD-1 blockade exerts its effect, leading to a response in this cohort [33]. MSI patients are known to selectively highly up-regulate expression of multiple immune checkpoints, including PD-1, PD-L1, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3) and indoleamine 2,3-dioxygenase (IDO) [34]. Limitations to this trial were small patient numbers (n = 41), and an MSI cohort that contained mostly patients with Lynch Table 4 Clinical trials investigating the use of PD-1 antibodies in the neoadjuvant, adjuvant and advanced pancreatic cancer setting.…”