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 CRCpMMR displays 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 CRCpMMR is further supported by interferon gamma (IFN-?) unresponsiveness of both tumor cells and TAMs.Colorectal 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-?-modulation of PD-L1/CD274. Relevant findings were subsequently validated by immunohistochemistry on fixed materials. CRCpMMR contain 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-?. These findings confirm the immune suppressive microenvironment of CRCpMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion, and interferon-? unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCpMMR.

Immuno-Contexture and Immune Checkpoint Molecule Expression in Mismatch Repair Proficient Colorectal Carcinoma

Giacomelli, Mauro;Monti, Matilde;Lonardi, Silvia;Bugatti, Mattia;Missale, Francesco;Cioncada, Rossella;Melocchi, Laura;Villanacci, Vincenzo;Baronchelli, Carla;Manenti, Stefania;Imberti, Luisa;Vermi, William
2023-01-01

Abstract

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 CRCpMMR displays 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 CRCpMMR is further supported by interferon gamma (IFN-?) unresponsiveness of both tumor cells and TAMs.Colorectal 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-?-modulation of PD-L1/CD274. Relevant findings were subsequently validated by immunohistochemistry on fixed materials. CRCpMMR contain 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-?. These findings confirm the immune suppressive microenvironment of CRCpMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion, and interferon-? unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCpMMR.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/596921
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