Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens

Abstract

The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO+ memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations.

Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms

“…In order to assess the immune response against CALRLong36, we used IFN-g ELISPOT assays performed on PBMCs as described in detail earlier (37). In short, PBMCs were thawed and stimulated with CALRLong36 and then stimulated with IL-2 (120 U/mL) the next day.…”

Contribution of pre-existing neoantigen-specific T cells to a durable complete response after tumor-pulsed dendritic cell vaccine plus nivolumab therapy in a patient with metastatic salivary duct carcinoma

“…Recently, it was reported that neoantigen-reactive T lymphocytes are also present in healthy individuals (Holmström et al 2019;Holmström and Andersen 2020). For example, the presence of T lymphocytes that respond to neoantigen peptides by K-RAS mutation was also demonstrated in healthy individuals (Holmström and Andersen 2020). The presence of neoantigen-reactive T cells before the start of immunotherapy for cancer and possibly before the onset of cancer is an interesting finding, and further research in this field is expected in the future.…”

“…Our retrospective study also suggested the involvement of neoantigen-reactive T lymphocytes that were present before treatment. Recently, it was reported that neoantigen-reactive T lymphocytes are also present in healthy individuals (Holmström et al 2019;Holmström and Andersen 2020). For example, the presence of T lymphocytes that respond to neoantigen peptides by K-RAS mutation was also demonstrated in healthy individuals (Holmström and Andersen 2020).…”

Prophylactic vaccines against cancers of non-infectious origin: a dream or a real possibility?

“…This undertaking should be aimed at examining the validity of the "3Es" (94) hypothesis. To the best of our knowledge, the presence and distribution of the immune reactivities to the mutated RAS and RAF oncoproteins in a general population has not yet been reported, although the presence of immune responses to mutated RAS epitopes has been demonstrated (83). We therefore propose to select groups of ten to twenty unvaccinated healthy volunteers belonging to different age groups (21-30, 31-40, 41-50, 51-60, and so on) for such an investigation.…”

“…While major support for the present concept of prophylactic anti-cancer vaccine development stems from experiments in a mice model, a strong backup for this concept has quite recently been provided by the demonstration of immune responses to mutated RAS epitopes in healthy subjects (83). This provides a strong support for the assumption that these healthy individuals experienced contact with cells expressing the respective RAS mutations earlier in their lives but have been capable of effectively controlling the neoplastic process.…”