Cancer Cells Alter HLA To Escape CTL

Despite progress made, cancer remains tough to treat, especially high-grade and late-stage cancer. These are manifested by cancer relapse as well as drug resistance which contribute to less optimal overall survival for cancer patients. One active area of research to tackle these challenges is the focus on cancer immune escape. Cancer cells escape immune surveillance by altering HLA through loss of heterozygosity, reduced gene expression level, or both. Here we shall focus on Class I classical HLA molecules comprised of HLA-A, HLA-B, and HLA-C proteins.

As discussed in our previous topic, the nemesis of cancer cells is the cytotoxic T lymphocyte or CTL. Hence, escaping CTL is a high priority for cancer survival. Cancer cells can hold CTL “at bay” through loss of heterozygosity (LOH). LOH is defined as the loss of one of the two alleles of a gene. (This may occur through mutation.) LOH of HLA, especially with classical class I genes/HLA antigens, is a major event associated with multiple cancer types including lung, colon, breast, and brain cancer. In light of the pivotal role HLA plays in activating CTL, LOH of HLA impedes CTL activation and is accordingly negatively associated with cancer patients' overall survival.

In addition to occurrences of LOH at cancer onset, LOH of HLA has also been reported to occur in response to cancer treatment. At a US National Institutes of Health (NIH) clinical trial to assess the efficacy of immunotherapy in metastatic cancers⁴, all patient participants were screened for HLA antigens prior to the immuno-therapeutic procedures. The procedure involved collecting cytotoxic T cells (CTL) from each patient, editing the patient-specific CTL to recognize one’s own cancer antigens, and then returning the edited CTL back to the patient. One patient showed tumor relapse and upon genomic examination, it was revealed that one of the HLA antigens termed HLA-C*08.02 was lost in response to the immunotherapy. (Note: In genetics nomenclature, the asterisk in the name implies an allele - an alternate form of the gene.) A plausible speculation for the HLA loss was that the selective pressure exerted by patient tumor antigen-specific CTL prompted cancer cells to undergo a genetic change (of losing HLA-C*08.02) to favor cancer cell evasion of CTL surveillance and subsequent elimination.