N29: New Treatment Possibilities For Lynch Syndrome-Associated Cancer?

J. Walkowska1, T. Kallemose1, G. Jönsson2, M. Jönsson2, O. Andersen1, M. H. Andersen3, I. M. Svane3, A. Langkilde1, M. Nilbert1, 2, 4, C. Therkildsen1

1 -The Danish HNPCC register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark. 2 – Institute for Clinical Science, Department of Oncology and Pathology, Lund University, Sweden. 3 – Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark. 4 – The Danish Cancer Society Research Center, Copenhagen, Denmark.

 

Aim: Recent advances within immunotherapy have proven highly effective in microsatellite instable tumors, which offer promising treatment options for Lynch syndrome patients. However, different immune evasion mechanisms may influence the response rate and call for further investigation in Lynch syndrome tumors.

Method: We examined the immunological tumor microenvironment and potential immune-escape mechanisms and ana-lyzed their prognostic value in 169 Lynch syndrome-associated colorectal cancers with comparison to 101 mi-crosatellite stable tumors.

Results: Lynch syndrome cancers where dominated by increased infiltration of CD3+ T cells, CD8+ cytotoxic T cells and CD68+ macrophages and showed up-regulation of pro-inflammatory genes suggestive of an immune-mediated surveillance and potential tumor-killing. Interestingly, two escape mechanisms were also found up-regulated in Lynch syndrome tumors, which related to loss of the MHC class I subunit, Beta-2-microglobulin (B2M), and T cell exhaustion through up-regulation of PD-L1. Immune evasive tumors showed up-regulation of genes involved in natural killer cell-mediated cytotoxicity and cell death indicating that additional immunological cell types may aid in the eradication of tumor cells. This was supported by survival analyses showing improved survival in patients with PD-L1 positive and B2M negative tumors.

Conclusion: These data suggest that detailed immunological characterization could predict immunotherapy response and should be performed prior to immune therapy.

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