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A low neoantigen expression and T-cell dysfunction are critical for early immune escape and clinical response in colorectal cancer
Patients with microsatellite stable colorectal cancer express neoantigens, but they are broadly expressed at lower levels and this precludes productive cross-priming of T-cells, which drives immediate T-cell dysfunction and an early immune escape. These are the results of a recently published paper in Nature Cancer, showing also that therapeutic rescue of priming is possible and renders T-cells capable of controlling tumors with low neoantigen expression.
Authors studied neoplasies from over 400 patients to understand the mechanisms of low immunogenicity in colorectal cancer with stable microsatellites and low mutagenicity; these tumors has on average more mutations than some cancers that respond favorably to therapy with immune checkpoint inhibitors, so there must be specific factors, both tumor intrinsic and microenvironmental, which contribute to the poor immunogenicity. To identify and study them in detail, the researchers used organoids and tumor transplantation into the distal colon of mice, models that both have proved to faithfully recapitulate the tissue microenvironment and genetics of the human diseases. Data analysis shows that in colorectal tumors with stable microsatellites and with low mutagenicity there is a production of tumor neoantigens, but at lower levels than in tumors with microsatellite instability and high mutagenicity; this low expression of neoantigens results in poor activation of the T cell response and in the dysfunction of the T cells themselves, ultimately leading to an early immune response escape.
The good news is that priming of T cells can be recovered: neoantigen vaccination in mice with established tumors induced profound expansion of tumor-specific T cells in peripheral blood and a reduction in tumor mass. Good results were also obtained with antibodies against the CD40 receptor (which enhance priming by potentiating the co-stimulatory function of antigen presenting cells) used in combination with anti-PD-1 and anti-CTLA-4; the combinations also reduced the rate of metastasis. «The flexible organoid-based system we have developed should facilitate a broad range of future studies by providing a powerful preclinical platform for evaluating new immunotherapies», authors say.