Therapeutic strategies to remodel immunologically cold tumors

Abstract

Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these 'responsive' tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near-complete absence of lymphocytes from the tumor, so-called immunologically cold tumors. Here, we propose two broad approaches to convert 'cold' tumors into 'hot' tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor-beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen-presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.

Keywords: cancer immunotherapy; cold tumor; immune checkpoint inhibitor; immune surveillance and resistance; therapeutic strategy; tumor microenvironment.

Figure 1

Therapeutic strategies to remodel immunogenically cold tumors. (a) Features of an immunologically cold tumor. (b) Representative fluorescent images showing the cold and hot head and neck tumors with T infiltration visualised by CD3⁺ T cells (green) and a tumor marker (magenta). (c) Two therapeutic strategies that focus on inducing immunogenic tumor cell death and targeting the tumor microenvironment to convert ‘cold’ tumors into ‘hot’ ones. TGF‐β: Transforming growth factor‐beta.

Figure 2

The cancer immunity cycle and selective methods to increase tumor immunogenicity. Tumor antigens are released as cancer cells die and are captured by the antigen‐presenting dendritic cells in the tumor site, and further presented to T cells in the lymph node. T cells are activated and proliferate, and effector T cells traffic and infiltrate into the tumor site. Activated effector T cells recognise and kill the cancer cells. Oncolytic viruses/bacteria, conventional therapy and targeted therapies are able to induce immunogenic cell death. Personalised cancer vaccines typically comprise tumor‐associated antigens or tumor‐specific antigens in a vaccine vector (RNA, DNA, viral, bacteria, protein, peptide and antigen‐presenting cells) with an immune adjuvant. IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TCR, T‐cell receptor; TNF, tumor necrosis factor.