A frameshift-generated cancer neoepitope that controls tumor burden in prophylaxis as well as therapy

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Frameshift mutations caused by insertions or deletions (InDels) can create novel neoepitopes.
• These InDel-generated neoepitopes lack self-counterparts, offering a unique target for cancer immunotherapy.
• Previous studies showed InDel neoepitopes can elicit CD8 T-cell responses, but in vivo tumor control was not demonstrated.

Purpose of the Study:

• To identify and validate InDel-generated neoepitopes capable of controlling tumor growth in vivo.
• To investigate the characteristics and efficacy of a novel InDel-generated neoepitope.
• To compare the T-cell exhaustion profile of InDel-generated neoepitopes with those from point mutations.

Main Methods:

• Screening of 11 InDels in a mouse colon carcinoma line.
• Assessment of tumor control in vivo using prophylaxis and therapy models.
• Analysis of neoepitope affinity for MHC I alleles.
• Evaluation of CD8 T-cell responses and exhaustion levels.

Main Results:

• One of 11 identified InDels generated a neoepitope that mediated tumor control in vivo.
• This neoepitope, despite low MHC I affinity, elicited significant antitumor activity via CD8 T cells.
• CD8 T cells induced by this InDel neoepitope exhibited less exhaustion compared to those from point mutation-derived neoepitopes.

Conclusions:

• InDel-generated neoepitopes can elicit potent antitumor immunity in vivo.
• Novel InDel neoepitopes can control tumors even with low MHC I affinity, challenging previous assumptions.
• These findings highlight the therapeutic potential of InDel-generated neoepitopes in cancer treatment and suggest a less exhausted T-cell response.