Unexpected tumor reduction in metastatic colorectal cancer patients during SARS-Cov-2 infection: effect of ACE-2 expression on tumor cells or molecular mimicry phenomena? Two not mutually exclusive hypotheses.

Dear Editor,

We read with great interest the recent paper by Ottaiano et al. about unexpected tumor reduction in metastatic colorectal cancer patients following SARS-CoV-2 infection published in this journal. The authors describe three patients that underwent a significant reduction of the disease after mild to severely symptomatic COVID-19.

The authors hypothesize that this reduction might be due to the direct viral infection of tumor cells via the ACE-2 receptor (the cell’s gateway for the virus) because this receptor is expressed by a variety of human cytotypes, including colorectal ones. In turn, the entrance of the virus into the tumor cells would trigger an immune response against them.

This is a fascinating hypothesis that prompted us to propose another, different but not exclusive, which we recently published in another journal. We propose to consider a role for molecular mimicry, namely viral proteins mimic human molecules (e.g., molecular chaperones/heat shock proteins or Hsps) and, thus, elicit immunity not only against themselves but also against the human proteins expressed on the tumor cells. This would be a case of autoimmunity caused by foreign antigens against crossreactive epitopes on host’s cells.

SARS-CoV-2 may elicit autoimmunity in the host because of molecular mimicry of human proteins that share immunogenic epitopes with viral proteins. Among the human molecules that share epitopes with viral molecules are the chaperones Hsp60, Hsp70, and Hsp90. These chaperones are typically increased in colorectal cancer tissue, in which they are distributed with a pattern different from that characterizing normal cell counterparts, being also on the plasma-cell membrane and accessible to the immune system and, thus, can be targets for immunotherapy.[4-6]

We would like to prompt clinical studies to test the hypothesis that the disease reduction in patients affected by colorectal cancer is caused by an immune reaction against chaperones/Hsps initiated by SARS-CoV-2 infection through molecular mimicry. For example, serum from cancer patients ought to be examined to determine whether the levels of antibodies against chaperones/Hsps are different from those of proper controls and if they are cytotoxic/cytolytic for cancer cells. Other assays are possible, involving cells of the immune system and appropriate targets. Confirmation of this hypothesis would probably boost efforts to develop efficacious immunotherapy of cancer, in Coley’s footsteps of many years ago.