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Remodeling of the Immune and Stromal Cell Compartment by PD-1 Blockade in Mismatch Repair-Deficient Colorectal Cancer

ABSTRACT: Immune checkpoint inhibitor (ICI) therapy can induce complete responses in mismatch repair-deficient and microsatellite instability-high (d-MMR/MSI-H) colorectal cancers (CRCs). However, the mechanism responsible for pathological complete response (pCR) to immunotherapy has not been completely understood. We utilize single-cell RNA sequencing to examine the immune and stromal cell dynamics in 19 patients with d-MMR/MSI-H CRC treated with the neoadjuvant PD-1 blockade. In tumors with a pCR, the proportions of CD8+ Trm-mitotic, CD4+ Tregs, proinflammatory IL1B monocyte and CCL2+Fibroblast concertedly decrease following treatment, while those of CD8+ Tem, CD4+ Th, CD20+ B and HLA-DRA+ Endothelial cells increase. Proinflammatory features in tumor microenvironment mediate the persistence of residual tumors by modulating CD8+ T cells and other response-associated immune cell populations. Our study provides rich resources and biological insights into the mechanism of successful ICI therapy and potential targets to improve treatment efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205506 | GEO | 2023/05/11

REPOSITORIES: GEO

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Project description:Immune chekpoints (ICI) are evaluated in many digestive cancers. Certain types of cancer appear to be rather refractory to ICI such as colorectal cancers (CRC). However, the MSI CRC representing approximately 15% of the CRCs exhibits a high mutational load which generates many potentially immunogenic neoantigens. In addition, strong expression of PD-L1 was found in the MSI CRCs relative to the CRC (MSS) stages. Localized MSI CRCs have a better prognosis than MSS CRCs, probably due to immunogenic neoantigens associated with a CD8 + T-specific immune response. On the oher hand, in metastatic CRC (mCRC) things are different because i) the MSI frequency is only 4 to 7% and ii) the good prognosis conferred by the MSI status is controversial. Preliminary results suggest that patients with MSI mCRC are highly sensitive to ICI even chemoresistant tumors receiving several lines of chemotherapy. Recently, another anti-PD1 alone or in combination with an anti-CTLA4 (antigen associated with cytotoxic T-lymphocyte 4) was tested in the MSI CRCs and a selection of interesting results in heavily pretreated patients with a disease control rate of 56% for monotherapy and 81% for combinated therapy. Anti-PD1s now have marketing authorization for patients with melanoma and metastatic pulmonary carcinoma , Which are known to have a high level of mutations . ICIs appear to be as promising in MSI CRCs as in other tumors and therefore face the same major challenges. Avalumab is an anti-PD-L1 antibody recently tested in several different types of tumors with promising results and is currently being studied in phase III in gastric cancer. There is no data on the effectiveness of this ICI in the MSI mCRCs. In addition, only anti-PD1 was used in the MSI-mCRC and not the anti-PD-L1, and only in chemoresistance (3rd line or more). The main objective of the SAMCO study is to test the efficacy and tolerance of avelumab in the 2nd line of treatment in patients with a MSI mCRC progression after standard 1st line chemotherapy +/- targeted therapy.

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Remodeling of the Immune and Stromal Cell Compartment by PD-1 Blockade in Mismatch Repair-Deficient Colorectal Cancer

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