Simple SummaryConsensus Molecular Subtypes have recently been proposed based on molecular and immune landscape of colorectal carcinoma (CRC). Only mismatch repair deficient and hyper-mutated CRC (CRCdMMR) can obtain clinical benefits from immune checkpoint blockades; on the other hand, mismatch repair proficient CRCs (CRCpMMR) have very limited therapeutic options. This study establishes that CRCpMMRdisplays an immunosuppressive microenvironment containing abundant tumor-associated macrophages (TAMs) and neutrophils, with a reduction in double negative T lymphocytes and B cells and increased exhausted tumor-infiltrating lymphocytes. Poor immunogenicity in CRCpMMRis further supported by interferon gamma (IFN-γ) unresponsiveness of both tumor cells and TAMs.AbstractColorectal carcinoma (CRC) represents a lethal disease with heterogeneous outcomes. Only patients with mismatch repair (MMR) deficient CRC showing microsatellite instability and hyper-mutated tumors can obtain clinical benefits from current immune checkpoint blockades; on the other hand, immune- or target-based therapeutic strategies are very limited for subjects with mismatch repair proficient CRC (CRCpMMR). Here, we report a comprehensive typing of immune infiltrating cells in CRCpMMR. We also tested the expression and interferon-γ-modulation of PD-L1/CD274. Relevant findings were subsequently validated by immunohistochemistry on fixed materials. CRCpMMRcontain a significantly increased fraction of CD163+macrophages (TAMs) expressing TREM2 and CD66+neutrophils (TANs) together with decrease in CD4−CD8−CD3+double negative T lymphocytes (DNTs); no differences were revealed by the analysis of conventional and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells displays an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCpMMRcharacterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion, and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCpMMR.