The fallacy of tumor immunology: Evolutionary pressures, viruses as nature's genetic engineering tools and T cell surveillance emergence for purging nascent selfish cells

TL;DR

This paper challenges traditional views on tumor immunology, proposing that immune responses to cancer differ fundamentally from those to infections, emphasizing evolutionary perspectives and a one-signal T cell activation model.

Contribution

It introduces a novel one-signal model for T cell activation and reinterprets immune responses to cancer versus infection based on evolutionary and theoretical grounds.

Findings

Autoimmune adverse events in melanoma support the one-signal model.

Immune system evolved primarily for purging selfish cells, not pathogen defense.

Immunization against isogeneic tumors may be ineffective.

Abstract

The US and Hungarian statistical records of the years 1900 and 1896, respectively, before the dramatic medical advances, show 32% and 27% deaths attributable to infections, whereas only 5% and 2% due to cancer. These data can be interpreted to mean that (i) the immune system evolved for purging nascent selfish cells, which establish natural chimerism littering the soma and the germline by conspecific alien cells and (ii) defense against pathogens that represent xenogeneic aliens appeared later in evolution. `Liberating' T cells from the semantic trap of immunity and the shackles of the `two-signal' model of T cell activation, we point out theoretical grounds that the immune response to cancer is conceptually different from the immune response to infection. We argue for a one-signal model (with stochastic influences) as the explanation for T cell activation in preference to the widely accepted two-signal model of co-stimulation. Convincing evidence for our one-signal model emerged from the widespread autoimmune adverse events in 64.2% of advanced melanoma patients treated with the anti-CTLA-4 antibody (ipilimumab) that blocks an immune checkpoint. Harnessing the unleashed autoimmune power of T cells could be rewarding to defeat cancer. Assuming that immunization against isogeneic tumors also would be effective is a fallacy.