Thank you for submitting your questions and comments about the documentary Jim Allison: Breakthrough. We have answered them in this recorded video with the help of Patrick Ott, oncologist and clinical director of the Melanoma Disease Center and Center for Immuno-Oncology at the Dana-Farber Cancer Institute in Boston.
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All-trans retinoic acid overcomes solid tumor radioresistance by inducing inflammatory macrophages
Rao et al. showed that antitumor responses to irradiation (IR) are greatly enhanced when all-trans retinoic acid (RA) is co-administered to mice. Within 4 days of combination IR and RA treatment, increased intratumoral levels of iNOS- and TNF-α-expressing macrophages (Inf-MACS) were observed. This was followed by iNOS-dependent enhanced recruitment of tumor-specific CD4+ and CD8+ effector cells – both important contributors to the response. Inf-MACs and T cells function in a synergistic feedback loop to maintain a pro-inflammatory TME. PD-L1 blockade enhanced combination therapy, even in tumors distal to an irradiated tumor.
Contributed by Margot O’Toole
Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma
Although present in skin, innate lymphoid cells (ILCs) have not been fully explored as a therapeutic target in melanoma. Jacquelot et al. showed that high Group 2 ILC (ILC2) infiltration was associated with favorable outcomes in melanoma patients. In addition to IL-5 and -13, ILC2s produced high levels of GM-CSF in the TME, resulting in increased numbers of eosinophils with enhanced cytotoxicity. High levels of PD-1 expression on intratumoral ILC2s inhibited ILC2-driven antitumor efficacy, but could be overcome by treating in vivo with anti-PD-1, especially when combined with anti-CD33, a known ILC2 activator.
Contributed by Katherine Turner
VISTA is an activating receptor in human monocytes
Using two novel VISTA-specific antibodies, Rogers et al. showed high levels of VISTA on primary human blood monocytes. In an Fc-dependent manner, the antibodies were agonistic, leading to enhanced expression of mediators of antigen presentation, leukocyte migration, cell adhesion, DC differentiation, and cytokine signaling. Monocytes also specifically bound a pentameric construction of VISTA’s extracellular domain, and the heparan sulfate proteoglycan (HSPG) Syndecan-2 was identified as the VISTA binding partner. HSPGs can also bind certain chemokines, suggesting the possibility of cis and trans immune regulatory networks in monocytes.
Contributed by Paula Hochman
Distinct antigen uptake receptors route to the same storage compartments for cross-presentation in dendritic cells
Using a combination of pulse-chase, staining, visualization, and T cell stimulation techniques, Ho et al. showed that internalization of extracellular antigen in cDC1s and cDC2s via two different receptor pathways (FcγR and a lectin receptor (MLG1/CLEC10A)) transited the antigen to a novel, perinuclear compartment for extended storage prior to presentation. This compartment lacked the canonical endopeptidase Cathepsin S activity found in lysosomal vacuoles, but contained the carboxypeptidase Cathepsin X. Presentation of antigen from this compartment persisted for days, which may be important during DC migration and antigen transfer to LN-resident DCs.
Contributed by Ed Fritsch
TIM-3 restrains anti-tumour immunity by regulating inflammasome activation
Dixon et al. highlighted the immunosuppressive role of TIM-3 in DCs and demonstrated that TIM-3 blockade promoted inflammasome activation and antitumor immunity. TIM-3 deletion in DCs, but not on CD4+ and CD8+ T cells, reduced tumor growth in mice bearing MC38-OVAdim tumors, promoted maintenance of stem-like CD8+ T cells, and increased antigen-specific CD8+ T cells with higher levels of effector cytokines. Loss of TIM-3 in migratory DCs increased inflammasome- and oxidative stress-associated gene signatures, and treatment with antioxidant or anti-IL-1β/IL-18 abolished the protective antitumor immunity of TIM-3-deleted DCs.
Contributed by Shishir Pant
Diverse immune response of DNA damage repair-deficient tumors
To investigate the relationship between DNA damage repair deficiency (DDR-d) and response to immunotherapy, Qing et al. evaluated the association between alterations in DDR genes (germline/somatic mutations and methylation) with tumor neoantigens and immune infiltrates in 10,080 cancers from 32 cancer types. Mutations in homologous recombination genes were very frequently associated with higher TMB and neoantigen loads, and somatic DDR-ds were associated with tumor immune infiltration, higher neoantigen load, and better survival after immunotherapy, but these effects varied by cancer type. MLH1 deficiency classified neoantigen-high tumors for higher immunogenicity.
Contributed by Shishir Pant
