Immunoediting on the Brink: Dynamic Relationship Between Tumor Genotype and Microenvironment as Determinant of Immunotherapy Effectiveness in an informative case report of Lynch Syndrome

Abstract Background: Lynch syndrome is an autosomal-dominant inherited condition that significantly increases the risk of developing cancer; within the Lynch syndrome spectrum, Muir-Torre syndrome is an autosomal-dominant genodermatosis, associated with keratoacanthomas and sebaceous neoplasms (adenoma, carcinoma or epithelioma). Both are characterized by the presence of defects in mismatch repair genes resulting in the high mutational rate that accounts for elective sensitivity to immunotherapy with checkpoint inhibitors. However, up to 30% of patients experience refractoriness to treatment. Case presentation: This report describes a potentially informative case of a Lynch/Muir-Torre syndrome patient, who developed gastric cancer while in complete metabolic response to immunotherapy for metastatic duodenal carcinoma and cutaneous epithelioma. Both tumors exhibited high mutational rates and microsatellite instability. Deregulation of the TGF-β2 axis and absence of CD11c-positive dendritic cells in tumor microenvironment together with the loss of IL-8 expression on tumor-associated macrophages represent intriguing findings in this Lynch Syndrome-related immuno-refractory neoplasia. Conclusions: A comprehensive evaluation of the genetic features of tumor cells together with the assessment of intratumoral immune infiltrate may provide insights into the heterogeneous mechanisms of resistance to checkpoint inhibitors.