Page 1078 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 77 Immunotherapy of Cancer 1043

IFNγ receptor, which initiates signaling through the Janus kinase/
Resistance Mechanisms signal transducer and activator of transcription (JAK/STAT)
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Durable clinical responses with immune checkpoint therapy have pathway to regulate gene expression. Data from two independent
been well documented; some of these responses last for years. studies have established that the loss of genes involved in the
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However, many patients do not respond to initial therapy or IFNγ signaling pathway may lead to both primary and adaptive
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relapse with disease after initially responding to treatment. resistance to immune checkpoint therapy.
Resistance mechanisms may involve the following: (i) activation Previously published data from a study in patients with bladder
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of oncogenic pathways (WNT/B-catenin signaling, loss of PTEN cancer demonstrated increased frequency of a CD4 ICOS T-cell
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expression), (ii) loss of interferon-gamma (IFNγ) signaling genes, subset that produced IFNγ following anti-CTLA-4 therapy. We
(iii) recruitment of immunosuppressive cells such as Treg, further hypothesized that tumor cells harboring mutations in
myeloid-derived suppressor cells, M2 macrophages, and expression the IFNγ-signaling pathway are not susceptible to the IFNγ
of other inhibitory immune checkpoints, and (iv) composition produced by these T cells, which may result in resistance to
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of gut microbiome. anti-CTLA-4 therapy. Evaluation of genomic alterations of
IFNγ-pathway genes in melanoma patients treated with ipilim-
umab demonstrated that the tumors of the nonresponders had
KEY CONCEPTS loss of IFNγ-pathway genes at significantly higher frequencies
Mechanisms of Tumor Resistance to Immune- compared with the responders.
Mediated Therapy Furthermore, mice bearing melanoma tumors with knockdown
of IFNγ-receptor, resulted in impaired tumor rejection when
• Activation of oncogenic pathways treated with anti-CTLA-4 therapy.
• Loss of interferon-γ signaling genes in the tumor cells Similarly, another study compared paired tumor biopsies that
• Recruitment of immunosuppressive cells (e.g., Treg cells, myeloid-
derived suppressor cells) were collected from four melanoma patients before treatment
• Expression/secretion of inhibitory molecules with anti-PD-1 (pembrolizumab) and at the time of disease
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• Composition of the gut microbiome relapse. In two out of the four patients whose disease relapsed
after initial responses to pembrolizumab therapy, mutations were
detected in the genes encoding interferon-receptor–associated
Activation of Oncogenic Pathways Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), two critical
Recent research has identified an intricate interplay between components of the IFNγ signaling pathway.
oncogenic pathways and antitumor immunity. Taken together, these findings indicate that the loss of IFNγ
In one such study, the whole exome sequencing and gene signaling limits the effectiveness of the immune system to
expression profiling of melanoma biopsies revealed that tumor-cell eliminate tumor cells and induces resistance to immune check-
intrinsic activation of the WNT/β-catenin pathway correlates with point therapy.
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absence of T cells in the tumor microenvironment. Further
investigation in a genetically engineered autochthonous mouse Immunosuppressive Tumor Microenvironment
melanoma model confirmed that increased oncogenic β-catenin In addition to the above-mentioned genomic alterations in tumor
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signaling results in a failure to recruit CD8α and CD103 DC cells, other resistance mechanisms within the tumor microen-
populations in the tumor due to repressed expression of the vironment include Treg cells, myeloid-derived suppressor cells
chemokine CCL4. Consequently, mice with tumors expressing active (MDSCs), M2 macrophages, expression of other inhibitory immune
β-catenin responded poorly to anti-CTLA-4 and anti-PD-L1 therapy, checkpoints (TIM-3, LAG-3, VISTA), recruitment of inhibitory
compared with mice with tumors lacking β-catenin expression. 70 molecules/ligands (indoleamine dioxygenase [IDO], carcinoem-
Apart from the activation of active β-catenin, the loss of PTEN bryonic antigen-related cell adhesion molecule 1 [CEACAM1],
expression is a frequent event in melanoma, especially in tumors PD-L1), and the secretion of inhibitory cytokines (IL-10, IL-35,
with BRAF mutations. PTEN is a negative regulator of the PI3K-AKT transforming growth factor [TGF]-β); these may have a direct
pathway, and the complete loss of PTEN is associated with increased negative effect on effector T-cell function and hence contribute
signaling through this pathway, correlating with shorter OS in toward immunosuppression and resistance to immunotherapy. 76,77
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patients with advanced melanoma. A recent study in a melanoma
mouse model demonstrated that the loss of PTEN expression can Gut Microbiome
reduce the therapeutic activity of immune checkpoint therapy. Two independent preclinical studies reported that the composition
The study additionally demonstrated that a selective PI3K-β-isoform of the gut microbiome can contribute to the difference in
inhibitor could induce synergy with immune checkpoint therapy responses to immunotherapy in cancer patients. 78,79
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in the preclinical model. Similarly, findings in human melanoma One study compared the tumor growth in mice with distinct
specimens confirmed that the loss of PTEN correlates with exclusion gut microbiota and identified that mice that harbored the com-
of CD8 T cell in the tumor and increased PI3K activation. Impor- mensal Bifidobacterium species had enhanced spontaneous
tantly, patients with tumors lacking PTEN expression demonstrated antitumor immunity compared with mice with a different gut
poor clinical responses to anti-PD-1 therapy compared with patients microbiota composition. Importantly, the direct administration
with retained PTEN expression. 72 of the Bifidobacterium species into mice with established mela-
noma tumors improved tumor-specific immunity and response
Loss of Interferon γ Signaling to anti-PD-L1 therapy. 78
It is well established that IFNγ, a critical cytokine produced Similarly, another study in tumor-bearing mice and cancer
by T cells and other immune cells, plays a role in promoting patients demonstrated that the efficacy of anti-CTLA4 therapy is
innate and adaptive immune responses and in inhibiting associated with T-cell responses specific for the microbiota species
tumor cell proliferation. IFNγ functions by binding to the Bacteroides fragilis. The study reported that antibiotic-treated and