Cancer Immunology and Immunotherapy: From Defining Basic Immunology to Leading the Fight Against Cancer

ABSTRACT

The past decade has seen the advent and widespread use of several immunotherapeutic modalities that have markedly improved treatment outcomes for patients with various cancers. Nevertheless, the study of cancer immunology traces its roots back to the inception of modern immunology, and played a critical role in the of discovery of central immunological concepts and development of key technologies and methodologies and that have propelled advances in all areas of immunology.

KEYWORDS:

• Bispecific antibodies
• cancer immunology
• cancer immunotherapy
• CAR T-cells
• dendritic cells

The past decade has seen the advent and widespread use of several immunotherapeutic modalities that have markedly improved treatment outcomes for patients with various cancers. Nevertheless, the study of cancer immunology traces its roots back to the inception of modern immunology, and played a critical role in the of discovery of central immunological concepts and development of key technologies and methodologies and that have propelled advances in all areas of immunology. For instance, the discovery by Kohler and Milstein that myeloma cells can be fused with immunized B cells to generate immortalized hybridomas that can perpetually secrete monoclonal antibodies that bind defined antigens enabled the development of a myriad of foundational basic investigatory, diagnostic, and therapeutic applications (Milstein 1999). Additionally, the seminal tumor transplantation studies by George Snell and colleagues using inbred and congenic mouse strains defined the major histocompatibility locus (MHC) (Snell 1981). This led to the subsequent discovery that binding of the T cell antigen receptor (TCR) to cognate antigen is restricted by self-MHC (Zinkernagel and Doherty 1974) (HLA in humans (Ryder et al. 1981)), which has been central to understanding immunity to infectious diseases, autoimmunity, allergy, transplantation tolerance, and of course the development of cancer immunotherapies.

Given that the immune system principally evolved to neutralize infectious agents, and for decades standard of care cancer treatments included chemotherapy, radiation, surgery, and hormonal blockade, it was not clear until recently that the basic study of cancer immunology would ultimately advance clinical oncology. Further, basic discoveries in tumor biology spurred the development of promising new therapies designed to directly kill tumors via non-immunological mechanisms, such as inhibitors that target either oncogenic mutated tyrosine kinases (Druker et al. 2006; Flaherty et al. 2010) or factors that promote tumor angiogenesis (Abdollahi and Folkman 2010). It has thus been remarkable that immunotherapies have not only significantly advanced the clinical treatment of cancer, but also that “non-immunological” therapies such as radiation (Sharabi et al. 2015), chemotherapy (Apetoh et al. 2007), hormonal blockade (Adler 2007), and oncogenic kinase inhibition (Knight et al. 2013) work in part by promoting anti-tumor immunity.

Immune responses to infections occur through the coordinated actions of innate immune cells that acquire pathogen-derived antigens while being activated by common pathogen-associated molecular patterns (PAMPs), which then program adaptive B and T cells to secrete pathogen-specific antibodies or cytokines and other effector molecules that promote the cytotoxic killing of infected cells, respectively. Importantly, T cells also have the ability to recognize MHC-complexed peptide fragments processed from mutated self-antigens (i.e., neoepitopes) that arise in tumors (Brennick et al. 2017; Lurquin et al. 1989; Tran et al. 2017). Nevertheless, given that tumors arise from self and hence do not express PAMPs, tumor-specific T cells typically fail to develop sufficient effector functionality to control tumors, and rather tend to be suppressed by the same tolerance mechanisms that limit the ability of self-reactive T cells to cause autoimmunity (Adler and Vella 2013). Hence, T cell-based cancer immunotherapies generally work by overcoming some aspect of tumor-specific T cell tolerance.

Dendritic cells that present pathogen-derived peptide antigens complexed to MHC prime cognate T cells to undergo expansion and effector differentiation (Mellman et al. 1998). When dendritic cells acquire and present tumor antigens, however, the absence of PAMPs as well as exposure to suppressive factors can cause them to adopt a tolerogenic phenotype where they program tumor-specific T cells to become dysfunctional (Mihalyo et al. 2007; Scarlett et al. 2012). Based on the ability to load dendritic cells with tumor antigens under ex vivo culture conditions that promote optimal T cell priming capacity (Palucka et al. 2007), in 2010 the dendritic cell-based vaccine Provenge (sipuleucel-T) designed to treat castration-resistant prostate cancer was the first therapeutic tumor vaccine to receive FDA approval (Kantoff et al. 2010). The thematic article by Fu and colleagues (Fu et al. 2022) provides an update on the continuing efforts to improve the efficacy and extend the range of dendritic cell-based vaccines to treat a variety of cancers.

Tumor growth sometimes causes sufficient inflammation to induce dendritic cell activation and hence priming of tumor-specific effector T cells that subsequently migrate into the tumors. Nevertheless, the repetitive contact with tumor antigen causes these T cells to lose their cytotoxic capacity and become functionally exhausted (Wherry and Kurachi 2015). Since these exhausted T cells express high levels of checkpoint receptors such as CTLA-4, PD-1, and LAG-3 that suppress effector functionality, monoclonal antibody (mAb) antagonists to these checkpoint receptors or their ligands (i.e., checkpoint blockers) can restore tumor-specific T cell function and elicit meaningful therapeutic responses in a subset of patients with melanoma and other solid tumors (Baumeister et al. 2016; Sharma and Allison 2015; Tawbi et al. 2022). The thematic article by Koguchi and Redmond (Koguchi and Redmond 2022) describe a potential on-treatment biomarker that could guide adjustments in treatment regimens that maximize therapeutic responses for individual patients receiving checkpoint blockers or other immunotherapeutic mAbs.

The efficacy of checkpoint therapy is in part limited because only a subset of exhausted T cells can be functionally rejuvenated (Ghoneim et al. 2017; Miller et al. 2019; Yost et al. 2019). Additionally, tumor-specific T cells typically only comprise a minor fraction of tumor-infiltrating lymphocytes (TIL) (Scheper et al. 2019; Simoni et al. 2018). Strategies are thus being explored to activate non-specific TIL, since they are more abundant but less exhausted (Caushi et al. 2021). The thematic article by Long and colleagues (Long et al. 2022) discusses recent advances in the development of bispecific antibodies that simultaneously bind a surface antigen on tumor cells as well as the TCR on T cells to enable tumor-non-specific TIL to directly kill tumor cells in an MHC-non-restricted manner.

Another therapeutic modality that enables MHC-non-restricted tumor cell killing utilizes engineered T cells with chimeric antigen receptors (CARs) that recognize a tumor cell surface antigen in its natural form. CAR T-cells have proven highly effective in treating B cell malignancies (Lim and June 2017), although it has been difficult to adapt them for treating solid tumors, in part due to the challenge of finding suitable tumor cell surface antigens that are not expressed at appreciable levels in essential healthy tissues. Conejo-Garcia and Guevara-Patino (Conejo-Garcia and Guevara-Patino 2022) discuss exciting advances on this front that may soon make CAR T-cell therapy effective in treating various solid tumors.

Preceding much of the discoveries regarding the mechanisms of anti-tumor immunity that fueled the development of the immunotherapies mentioned above, in the 1970s Bacillus Calmette-Guerin (BCG) became a standard first-line treatment for non-invasive bladder cancer. The final thematic article by Ward Grados and colleagues (Ward Grados et al. 2022) covers new developments in how BCG and other immunotherapies are being combined to further enhance therapeutic efficacy in patients with bladder cancer.

It was not possible in these five thematic reviews to fully cover the many exciting and innovative approaches that are currently being pursued to develop new and improve existing cancer immunotherapies. Nevertheless, we hope they convey that our rapidly expanding understanding of how immune function is regulated is providing a plethora of opportunities to develop varied therapeutic strategies to combat a disease that has itself evolved numerous means to escape natural mechanisms of tumor control.

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