The that circumvent natural immunosurveillance to permit

immune system is normally poised to eradicate neoplastic cells, hence it is
apparent that tumors which nevertheless arise and become established in
immunocompetent individuals must – over the course of their life histories –
engage mechanisms that circumvent natural immunosurveillance to permit their
unbridled progression to clinically-manifest colonies. Research conducted
during the past three decades has exposed a panoply of pathways exploited by human
malignancies to evade immunological destruction. Most notably, inhibitory
immune checkpoints such as CTLA-4 and PD-1/PD-L1, which normally maintain peripheral
tolerance by disabling the activation and effector functions of autoreactive
T-cells, have been found to be co-opted in a majority of common cancer types. The
clinical deployment of monoclonal antibodies which neutralize these pathways has
represented a significant step forward in the quest to conquer cancer.

Unfortunately, a well-known contrivance of neoplasia is to continuously
evolve and become resistant to anticancer therapies, and observations of acquired
resistance to checkpoint blockade immunotherapy occurring in a substantial
proportion of patients enrolled in clinical trials – often months or years
after an initially productive response – should come as a sobering reminder of
the need to continuously identify resistance pathways to overcome.1 As
immunotherapy becomes increasingly more commonplace, we can fairly expect an
increase in the number of reported cases of relapse. It is imperative to begin
to consider combination or sequential strategies to overcome resistance at a
time when immunotherapy is becoming mainstream. Using PD-L1 expression as a
sole biomarker is arguably inadequate, as it is increasingly clear that not all
PD-L1-positive tumors respond to PD-1/PD-L1 antibodies, and even some PD-L1-negative
tumors regress during immunotherapy.2 To
distill the complexity of mechanisms which abet the formation of so-called ‘immunoresistant
niches’ – a term coined by Syn et al in
a recent review article 1 – the
authors proposed a conceptual framework encompassing ten major hallmarks of
cancer immunoresistance. The authors of further suggested that mechanisms of
acquired resistance parallel those which underpin intrinsic resistance to
immunotherapy, although subtle contextual nuances in the basis of the two
phenotypes ought to be appreciated.

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The first overarching mechanism proposed is that of a defective
tumor immunorecognition system, which subsumes the following concepts: (1) disabled
antigen presentation, (2) limited neoantigen repertoire (which itself could be
a consequence of immunoediting), and (3) insufficient diversity and abundance
of CD8 T-cells. Indeed, these three ideas correspond to the individual steps of
tumor antigen presentation and priming of the adaptive immune system, and the
notion that defective tumor immunorecognition restrains both natural and
therapy-elicited immunosurveillance is now well-recognized.3 Current
clinical research focuses on the combination of immune checkpoint inhibitors and
(DNA-damaging) cytotoxic chemotherapeutic agents. It may seem counter-intuitive
to employ cytotoxic agents in a strategy aimed at enhancing T-cell activation
and clonal expansion, as it could potentially attenuate immune cells and
responses required for antitumor immunity. Pre-clinical studies have
demonstrated that DNA-damaging agents have, in addition to their direct
cytotoxic effects, the added benefit of promoting immunogenicity. Enhanced
immunogenicity may be achieved through two mechanisms – directly promoting antigenicity
of the tumor through the disruption of DNA, and indirectly lifting
immunosuppression within the tumor microenvironment.4 Blank and
colleagues have described a spectrum of tumor immunogenicity – ‘inflammatory’
tumors tend to be responsive to checkpoint inhibition, limiting combination
therapy usage to tumors that have acquired resistance, whereas ‘immune
desert’-type tumors probably require the complementary effect of combination
therapy to achieve significant clinical effect.5

Nevertheless, cancer cells have a range of adaptive programs to limit
DNA damage induced by genotoxic agents, which are linked to innate and adaptive
immunity. Inhibiting these DNA-repair mechanisms may possibly enhance tumor
foreignness 4, but may
come at the price of dampening the effects of immune checkpoint inhibitors.
Combination therapy of anti-DNA-repair agents and immune checkpoint inhibitors
may be promising, due to its potential for reducing toxicity associated with
the latter, especially where high doses of checkpoint inhibitors are required
in resistant tumors.4

A second overarching mechanism proposed by Syn et al relates to the tumor
microenvironment and neovasculature, and encompasses the following three
concepts: (4) the immune contexture (i.e., extent of T-cell infiltration and
reactivity), (5) deregulation of immunometabolism, and (6) angiogenesis.1 Indeed,
cancer cells interact within a dynamic and stochastic microenvironment with
heterotypic cell types. An abundance of literature has emerged in recent years
describing how these ostensibly ‘normal’ cells in the tumor microenvironment
contribute to spatially-limited ‘immunoresistant niches’. For instance,
proangiogenic VEGF signaling features in tumors that are resistant to
immunotherapy, and the tumor neovasculature may play a role in selectively
culling assailing CD8 T-cells while posing a formidable physical barrier to
their extravasation. Crucially, vascular normalization with anti-angiogenic
therapies have shown promise in improving lymphocyte trafficking across the
endothelium and reversing immunotherapy resistance.1 Emerging
evidence also suggests that derangements of T-cell immunometabolism –
particularly due to hypoxia, high concentrations of tumor-derived lactic acid,
and scarcity of glucose and amino acids in the tumor microenvironment – can
encumber the activation and effector functions of antitumor T-lymphocytes.1 Identifying
biomarkers pertaining to the tumor microenvironment to predict response or
resistance immunotherapy thus represents a necessary – albeit challenging –
logical next step.

Aside from the contributions of defective tumor immunorecognition
and the tumor microenvironment and neovasculature to immunotherapeutic
resistance, a further four resistance mechanisms were enumerated: (7)
Insensitivity to immune effector molecules (e.g., IFN-? and FasL), (8) tumor
plasticity and stemness, (9) the enteric microbiome, and (10) co-option of alternative
immune checkpoints.1 The role
of epithelial-to-mesenchymal transition (EMT) in fostering tumor plasticity is
less well-known and warrants further discussion. Studies conducted in the past
have promulgated the notion that inflammation-driven tumor plasticity, which
may occur through EMT programs, are partly responsible for mediating
therapeutic resistance to cytotoxic drugs, targeted therapies and radiation
therapy. Thus, recent findings that inflammatory immune infiltrates may also –
however paradoxically – engender resistance to adoptive T-cell transfer or
checkpoint blockade immunotherapy through EMT programs perhaps should not come
as a surprise.1 In
addition, the role of the gut microbiota in dictating response to immunotherapy
has become the subject of intensive research in the past few months, with
multiple studies reporting correlations between various microbial
constellations with immunotherapy efficacy. Unfortunately, these associations
have not been consistent across studies, and various points of conjecture exist
as to how gut bacteria may modify immunotherapy response and resistance. Until
such a time when the mechanisms of how enteric bacteria modulate the
adjuvanticity of immune response is fully elucidated, it seems unlikely that
rational approaches can be devised to harness the enteric microbiome to salvage
resistance to cancer immunotherapy.

Enumerating the multifactorial mechanisms through which resistance
to immune checkpoint blockade occurs may just be half the battle won. We have
discussed the importance of having frameworks to understand the plethora of
mechanisms at play in developing resistant tumors, and having biomarkers to
predict the likelihood of response and gauge the extent of response, if any. Identifying
these functional barriers to immunotherapy is critical to protract the efficacy
of immunotherapy, or enable immune checkpoint blockers to impinge on
previously-intractable malignancies. It is also important to consider other
current issues and future perspectives in the management of patients treated
with immunotherapy. The wide-range of adverse effects documented with
immunotherapy, from gastrointestinal upset to autoimmune inflammatory
conditions, hints at possible pharmacogenomic underpinnings and itself represents
a unique and ongoing challenge. For future research, it is important that clinical
development of checkpoint blockade immunotherapy continues to embrace parallel
developments in genomics and precision medicine. Like targeted therapies, we envisage
that optimal use of cancer immunotherapy will hinge on the identification of mechanistic
biomarkers of response and resistance, and this in turn underscores the
importance of conceptual frameworks – such as those discussed in the present Editorial – for conceiving the cancer-immunity
interplay, and to guide research agendas over the next decade.

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