Table 1.
Critical questions to address in future investigations of resistance to ICIs.
| Resistance node | Critical questions |
|---|---|
| Oncogenes and oncoproteins | How do functional “driver” mutations influence the immune repertoire and tumor immunogenicity? |
| Do driver mutations influence antigen presentation, CD8+ T-cell priming, and CD8+ T-cell tumor infiltration? | |
| How do comutations in tumor suppressors influence response and/or resistance to therapy? | |
| Is there a hierarchy among comutations, and are their effects direct or indirect? | |
| Genetic and epigenetic dysfunction | What is the combined frequency and degree of HLA class I loss across tumor histologies? |
| Are HLA class I loss patterns clustered by mechanisms of action? What are the triggers for loss? | |
| How do tumors subvert HLA class I loss? | |
| What is the timing of HLA class I loss in the context of a primary tumor vs. metastatic disease? | |
| Loss of sufficient and suitable antigens | Given HLA and antigen diversity, are there identifiable patterns that predict ICI resistance? |
| What features of the neoantigen-specific T-cell population are required for tumor clearance? | |
| Do neoantigens need CD4+ (HLA class II) and CD8+ (HLA class I) to circumvent resistance? | |
| Can epigenetic therapies reverse silencing and thereby boost neoantigen expression? | |
| What is the role of mutation-based neoantigens and intra/intertumor heterogeneity? | |
| Dysfunctional T-cell compartment | Which cell subsets are the primary influencers of ICI resistance? |
| How is T-cell “activatability” shaped after exposure to immunotherapy? | |
| Can the “state” of T-cell functionality be monitored continuously in vivo? | |
| Can costimulation be measured in vivo? | |
| What is the role for costimulatory pathways beyond CD28? | |
| What is the role of 4-1BB signaling in T-cell anergy and antitumor immunity? | |
| How can IFNγ sensitivity be utilized to identify patients who are potentially resistant to ICI? | |
| What aspects of IFNγ signaling directly affect ICI resistance and its relationship to disease stage? | |
| How interdependent are fluctuations in IFNγ signaling in the context of ICI resistance? | |
| What characterizes the antigen repertoire against a “successful” CD8+ T-cell memory response? | |
| Is there evidence of continual immunologic memory in long-term survivors? | |
| How is immunologic memory generated and dependent on a persistent T-cell memory clone? | |
| What interactions among immune subsets are needed to generate durable CD8+ T-cell memory? | |
| Lack of inflammation in the TME | Are the immune-excluded and immune-desert phenotypes sufficiently defined? |
| Does the tumor cell of origin affect the different mechanisms underlying the cold phenotypes? | |
| Does the spatial positioning of immune cells dictate or influence resistance to ICI therapies? | |
| What key influencers of trafficking and infiltration can be therapeutically targeted? | |
| Are there dominant chemokine networks within TME that promote ICI resistance? | |
| Are the mechanisms of immune exclusion uniquely influenced by various therapies? | |
| Deregulated tumor immunometabolism | How does therapy induce immune metabolic signature switching toward ICI resistance? |
| Does resistance involve modified mitochondrial biogenesis and immunometabolism plasticity? | |
| Can longitudinal metabolic signatures of circulating cancer and immune cells predict resistance? | |
| Can immunometabolism-based resistance be correlated with TME and immune infiltrate? | |
| Influence of the microbiome | Is the gut microbiome predictive of patient resistance to ICI treatment? |
| Can we modulate the gut microbiome to improve immune capacity and “fitness”? | |
| Can specific clusters of microbes predict, prevent, and/or stop ICI resistance? | |
| Does the gut microbiome affect toxicity to ICI? | |
| Inept host immunity | What is the impact of lymphocyte count and humoral factors (CRP and LDH) on ICI resistance? |
| How do subclinical chronic infections and inflammation shape resistance to immunotherapy? | |
| What are the effects of hormones and prostaglandins? | |
| How is immune capacity defined, and can it serve as a clinically meaningful measure of resistance? |
Abbreviations: CRP, C-reactive protein; LDH, lactate dehydrogenase.