The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Basic and Translational Cancer Immunology co-Section Editor Dr. Eric Tartour.
“Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity” by Pietro Fontana et al
Cell (2024)
Abstract:
Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.
Why this matters:
Pyroptosis is an immunogenic cell death that may promote antitumor immunity. The authors identified a small molecule agonist (DMB) of gasdermin D (GSDMD) that induces pyroptosis. Vaccination with DMB-treated cancer cells protects mice against secondary tumor challenge and synergizes with anti-PD1 via an immune-mediated mechanism.
“Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint” by Hsiao-Wei Tsao et al
Immunity (2024)
Abstract:
The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8+ T cells and natural killer (NK) cells. In vivo suppression screens revealed that Erap1 deletion inactivated the inhibitory NKG2A-HLA-E checkpoint, which requires presentation of a restricted set of invariant epitopes (VL9) on HLA-E. Loss of ERAP altered the HLA-E peptidome, preventing NKG2A engagement. In humans, ERAP1 and ERAP2 showed functional redundancy for the processing and presentation of VL9, and loss of both inactivated the NKG2A checkpoint in cancer cells. Thus, loss of ERAP phenocopies the inhibition of the NKG2A-HLA-E pathway and represents an attractive approach to inhibit this critical checkpoint.
Why this matters:
Loss of ERAP in tumors enhances NK and CD8+ T cell cytotoxicity and immune checkpoint blockade response. This loss also changes the peptide associated with HLA-E and required for NKG2A recognition. Loss of ERAP phenocopies inhibition of the NKG2AHLA
E pathway.
“Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer” by Camila Robles-Oteíza et al
J Exp Med. (2024)
Abstract:
Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.
Why this matters:
Hypoxia is a hallmark of many cancers. In both preclinical models and humans, the authors identified a hypoxia signature associated with resistance to immune checkpoint inhibitors. They also use a hypoxia-activated prodrug to partially counteract this resistance pathway.
“A STAT3–STING–IFN axis controls the metastatic spread of small cell lung cancer” by Aleks C. Guanizo et al
Nat Immunol. (2024)
Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion. This occurs because STAT3 is crucial for maintaining the immune sensor stimulator of interferon (IFN) genes (STING). Without STAT3, the cyclic adenosine monophosphate-guanosine monophosphate synthase-STING pathway is inactive, resulting in decreased type I IFN secretion and an IFN gene signature. Importantly, restoration of IFN signaling through re-expression of endogenous STING, enforced expression of IFN response factor 7 or administration of recombinant type I IFN re-established antitumor immunity, inhibiting metastatic SCLC in vivo. These data show the potential of augmenting the innate immune response to block metastatic SCLC.
Why this matters:
STAT3 is overexpressed in >50% of tumors, including SCLC. Deletion of STAT3 inhibits primary tumor growth, but paradoxically promotes metastasis. This metastatic escape mechanism could be overcome by restoring IFN signaling through re-expression of endogenous STING, which is silenced by STAT3 deletion. This is an example of how to better integrate complex opposing activities on tumor and immune cells of a potential tumor target (STAT3).