Tumor Immune Response

The Tumor Immune Response is a complex process that unfolds in three distinct stages. The first stage is elimination, where the immune system identifies and eradicates tumor cells that express strong neoantigens. Following this, the process enters the equilibrium stage. Here, the immune system manages to control the growth of the remaining immunogenic tumor cells by inducing a state of immune-mediated dormancy in them. Finally, the process reaches the escape stage. At this point, the immune system loses its ability to control the growth of edited tumor cells, leading to the progressive expansion of tumors that become clinically apparent. This stage also involves the establishment of an immunosuppressive tumor microenvironment (7).

Elimination phase / Hot tumors:

The elimination phase relies heavily on CD4+ and CD8+ Cytotoxic T Lymphocytes (CTLs) targeting tumor antigens. The immune system can control tumor growth and influence tumor immunogenicity, highlighting the crucial role of T cells in this process (7). T cells can generate antigen-specific responses against tumor-specific mutant neoantigens. A 2012 study on the d42m1 MCA sarcoma line demonstrated that CD8+ T-cell responses target a mutation in the spectrin beta2 protein. Experiments in wild-type mice revealed that tumor variants escaping immune elimination lacked this neoantigen. Further studies with oncogene-driven tumor models confirmed that outgrown tumors in wild-type mice lacked T-cell-targetable antigens. Human studies also showed loss of neoantigen expression in recurrent metastatic lesions after adoptive cell transfer treatment. These findings indicate that the adaptive immune system can recognize and eliminate tumor cells based on strong tumor antigen expression (7, 8).

Equilibrium phase / Immune-intermediate:

The equilibrium phase of the tumor immune response refers to a prolonged intermediate stage where the immune system and tumor cells coexist in a dynamic balance without complete tumor eradication or uncontrolled growth (9). Cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and cytokines such as Interferon Type II (IFN Type II) / Interferon Gamma (IFN-g) continue to exert selective pressure on tumor cells. Tumor cell populations that survive this pressure are often those with reduced immunogenicity, meaning they express fewer recognizable tumor antigens or major histocompatibility complex (MHC) molecules. This leads to a balance between immune-mediated tumor killing and tumor cell proliferation, keeping the tumor in a clinically undetectable or dormant state (10, 11). This phase can last for years and represents a tumor dormancy state governed by immune surveillance and immune evasion mechanisms. Genetic and epigenetic changes accumulate in tumor cells during this time, which may eventually give rise to variants capable of escaping immune detection—marking the transition to the escape phase, when clinically apparent cancer develops (9, 11). Understanding the equilibrium phase has significant implications for immunotherapy design. Maintaining or restoring this balance - effectively keeping cancer in a state of immune-controlled dormancy - is an emerging therapeutic goal. Strategies that enhance the cytotoxic immune response or prevent immune suppression may prolong equilibrium, preventing relapse or metastasis after treatment (12).

Escape phase / Cold tumors:

This is a broad term encompassing all immune system activities related to tumors, including both pro-tumor and anti-tumor mechanisms, including:

• immunosuppressive elements like regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) that promote tumor growth (1, 2 ,3).


• Involves immune tolerance mechanisms that allow tumors to evade detection, such as HLA downregulation and checkpoint molecule expression (e.g., PD-1, PD-L1, CTLA-4) (2, 3, 4, 5).


• May involve autoimmune-like features in the tumor microenvironment without clinical autoimmunity (6).

References:

(1) Ostrand-Rosenberg 2008
(2) Medler et al. 2015 Trends Cancer 1(1): 66-75
(3) Gonzalez et al. 2018 Genes Dev. 32(19-20): 1267-1284
(4) Munhoz & Postow 2016 F1000Res 5: 2545
(5) Mejía-Guarnizo et al. 2023 Front Immunol 14: 1298571
(6) Soussan et al. 2024 Front Immunol 15: 1343020
(7) Alspach et al. 2019 Cold Spring Harb Perspect Biol 11: a028480
(8) Matsushita et al. 2012 Nature 482: 400-404
(9) Calì et al. 2017 Open Biol 7(4): 170006
(10) Croci et al. 2007 Cancer Immunol Immunother 56(11): 1687-700
(11) Kim et al. 2007a Immunology 121(1): 1-14
(12) Atsou et al. 2021 PLoS ONE 16(11): e0259291

see also:
Anti-tumor immune responses
Anti-tumor T Cell Function
Cancer Immunotherapy / Immuno-Oncology
Cold tumors
Hot tumors
Immune checkpoint inhibitors (ICIs)
Immune Checkpoint Receptors