Tumor cells with altered self

Tumor cells with altered self refers to a fundamental concept in cancer immunology where malignant cells are recognized by the immune system due to changes in their surface-presented antigens. This concept is based on the altered self hypothesis, which states that T cells do not recognize foreign antigens alone but rather as a complex with self-Major Histocompatibility Complex (MHC) molecules (Zinkernagel & Doherty, 1974). In cancer, this altered self state is created by the presentation of neoantigens (mutated self-proteins), overexpressed self-antigens, or an altered repertoire of peptides that distinguish the tumor from healthy tissue (Schumacher & Schreiber, 2015). Natural Killer (NK) cells also participate in this recognition by detecting the missing self (loss of MHC-I) or altered self (stress-induced ligands or altered peptide-MHC complexes) on the tumor surface (Carrillo-Bustamante et al., 2017). Therapeutic interventions, such as immune checkpoint inhibitors like pembrolizumab and TCR-engineered T-cell therapies like afamitresgene autoleucel, aim to exploit these alterations to trigger a targeted anti-tumor immune response (D'Angelo et al., 2018). However, the primary challenge in targeting these cells is the risk of on-target, off-tumor toxicity and systemic autoimmunity if the targeted altered signals are shared with normal tissues.

Other names

Altered selfAltered self-antigen presentationNeoantigen-presenting tumor cellsMHC-restricted tumor recognitionAltered self-MHC complex

Therapeutic agents target these cells by enhancing the immune system's ability to recognize and eliminate cells presenting 'altered self' signals. This is primarily achieved through the blockade of inhibitory checkpoints (e.g., PD-1, CTLA-4) that tumors use to evade immune detection, or through the use of engineered T-cell receptors (TCRs) and bispecific molecules that specifically bind to altered MHC-peptide complexes on the tumor surface.