The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
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Westcott, P.M.K., Sacks, N.J., Schenkel, J.M. et al. Nat Cancer 2, 1071–1085 (2021).
“This is an excellent paper that uses several model systems to decipher neoantigen characteristics that affect their immunogenicity as well as their cross priming. It has strong ramifications on our understanding of immune evasion and therapy response.”
EACR Board
Summary of the findings
Immune checkpoint blockade immunotherapy is remarkably effective in patients with DNA mismatch repair-deficient colorectal cancer owing to a high burden of somatic mutation-derived antigens, or “neoantigens”. Unfortunately, most colorectal cancer—so called mismatch repair-proficient—is not responsive to these therapies. While these tumors harbor a lower burden of neoantigens than their mismatch repair-deficient counterparts, we showed that they are not devoid of neoantigens, harboring more mutations on average than some cancers that are responsive to immunotherapy. Interestingly, we found that neoantigens in mismatch repair-proficient colorectal cancer are expressed at lower levels on average, raising the possibility that neoantigen expression is also an important determinant of immunity. To functionally test this, we developed a versatile platform for modulating neoantigen expression in colorectal cancer organoids and transplanted these into the distal colons of mice. We showed that low expression of model neoantigens drove suboptimal T-cell cross-priming, and while neoantigen-specific T cells were observed infiltrating tumors, they underwent immediate functional impairment and failed to restrain tumorigenesis. Immune checkpoint blockade was minimally effective in the model, suggesting that this type of T-cell dysfunction is distinct from T-cell “exhaustion”. In contrast, therapies that boost priming (i.e., vaccination and agonistic anti-CD40) were highly efficacious.
Future impact of the findings
A major takeaway from this study is that not all T-cell dysfunction in cancer is the same. The dysfunction we observed is consistent with tolerogenic priming, which will require a different therapeutic approach. Neoantigen expression level (and likely other variables that affect MHC-I presentation) really tunes the quality of the initial T-cell response. This has important therapeutic implications, as immune “cold” tumors may harbor “Trojan horse” neoantigens that never primed productive T-cell responses and thus fly under the radar of functional tumor-infiltrating lymphocyte assays. But if priming can be rescued, these same neoantigens may render tumors vulnerable to killing.
