Blogs

It is my pleasure to welcome you to the latest edition of the JITC Digest. While I am honored to step into the role of Interim Editor-in-Chief, I must first send my sincerest thanks and appreciation to Founding Editor-in-Chief Pedro J. Romero for his guidance and dedication during his decade plus leading the journal. I encourage you all to view the special feature below, a thank you to Dr. Romero on behalf of JITC‘s Editorial Board and staff.

As JITC now opens a new chapter and enters its second decade, I am pleased to welcome Sjoerd van der Burg as Interim Deputy Editor-in-Chief. I look forward to working closely with him as we carry on the high quality and stellar reputation of the journal into a bright future. 

Change may be in the air at JITC, but unchanged is the commitment to continue publishing the best the immunotherapy field has to offer. Be sure to check out some of the top recent publications featured here in the Editor’s Picks. From identifying a population of CD163-expressing M2-like macrophages as key suppressors of T cell immunity with Marit J. van Elsas et al to a phase I, first-in-human trial that provides proof of principle that vaccination combined with checkpoint blockade may elicit antitumor T cell responses against prostate cancer by Karen A. Autio et al, there is something for everyone.

Finally, I would also like to thank the many of you who stopped by the SITC booth for the Meet the Editor activity during AACR 2023. It is always wonderful to see so many colleagues and discuss the latest science. If you couldn’t make it, join me at ASCO 2023 on Sunday, June 4^th. I will be available for a Meet the Editor activity at 11am CT at the SITC booth (#2016). I hope to see you there!

JITC Editor Picks

AN ANTI-MESOTHELIN TARGETING ANTIBODY DRUG CONJUGATE INDUCES PYROPTOSIS AND IGNITES ANTITUMOR IMMUNITY IN MOUSE MODELS OF CANCER

Microtubule-targeting agents such as auristatins and mayatansines modulate anti-tumor immunity via induction of dendritic cell maturation, proinflammatory cytokines, and T cell priming. Nicole L Wittwer and colleagues provide the first evidence that a mesothelin-targeting antibody drug conjugate (ADC) carrying the microtubule targeting payload tubulysin causes pyroptosis in tumor cells, resulting in disease control and immunologic memory in murine models. In vitro, the ADC killed breast and colon cancer cell lines in a dose-dependent manner as well as caused upregulation of the maturation markers MHC-II, CD40, CD80, and CD86 when bone-marrow derived macrophages were cocultured with tumor cells. Pyroptosis in the treated cultures was evident as membrane ballooning, loss of membrane integrity, release of LDH, and cleavage of both gasdermin E (GSDME) and caspase-3. Treatment with the ADC significantly controlled tumor growth in orthotopic mouse models, with the animals that were cured resisting rechallenge. Strikingly, delayed tumor growth and immunologic memory was even observed with a non-mesothelin-targeting control ADC, indicating the tubulysin payload may kill tumor cells and modulate immunity by bystander effects. Although the overall numbers of infiltrating T cells were unchanged by treatment with the ADC, the ratio of CD8⁺ to CD4⁺ T cells significantly increased. Tumor-specific knockout of GSDME eliminated all anti-tumor efficacy of the ADC in mice, yet co-treatment with recombinant Flt3 completely rescued survival benefits. These findings demonstrate immunologic modulation by an ADC, establishing the groundwork for future combination approaches to leverage the immune-modifying effects with the precise cytotoxic payload delivery enabled by these agents.    

INVASIVE MARGIN TISSUE-RESIDENT MACROPHAGES OF HIGH CD163 EXPRESSION IMPEDE RESPONSES TO T CELL-BASED IMMUNOTHERAPY

Research

Summary:

Myeloid lineage cells are known to play a key role in resistance to immunotherapy, but the precise mechanisms and cell populations responsible for impaired antitumor responses are incompletely characterized. Using comprehensive profiling of the immune infiltrate during a well-established murine model of therapeutic vaccine-induced regression of HPV-driven tumors, Marit J van Elsas and colleagues identify a population of CD163-expressing M2-like macrophages as key suppressors of T cell immunity. In mice with established TC-1 tumors, vaccination with the HPV E7 E7_43-63 synthetic long peptide, CpG, and Incomplete Freund’s Adjuvants in the contralateral flank results in a short period of tumor growth prior to incomplete regressions. High dimensional flow cytometry analysis of tumor and immune cells from mice vaccinated with this strategy revealed dramatic shifts in the lymphocytic and myeloid compartments over 3 days after the onset of tumor regression. Spatial profiling of tumors from mice treated with a specific inhibitor of the regulator of myeloid cell differentiation Csf1 revealed almost complete elimination of tumor-resident macrophages, yet a population of high CD163-espressing macrophages expressing the M2 markers Arg1, Egr2, PD-L1, SIRPalpha, and SiglecG persisted at the invasive margin. Selective depletion of this CD163-expressing population using doxorubicin-loaded liposomes enhanced the antitumor efficacy of therapeutic vaccination and shifted the phenotype of tumor-infiltrating CD8⁺ T cells. Inhibition of heme oxygenase 1—a key enzyme in wound healing that promotes release of anti-inflammatory metabolites such as iron, carbon oxide, and biliverdin—in combination with depletion of the CD163-expressing macrophages improved the efficacy of therapeutic vaccination, resulting in fewer relapses and prolonged survival. Analogous subsets of moncytic cells to these CD163-expressing macrophages were identified in humans based on transcriptional profiling, opening the door to developing strategies for targeting this population to reverse immunotherapy resistance. 

CD47 EXPRESSION IS CRITICAL FOR CAR T-CELL SURVIVAL IN VIVO

Research

Summary:

CD47 is highly expressed on several solid tumors, providing a “don’t eat me” signal that inhibits macrophage phagocytosis through an interaction with SIRPalpha. In characterizing a CD47-directed chimeric antigen receptor (CAR) T cell, Alex N Beckett and colleagues demonstrate that CD47 is required for CAR T cell persistence and efficacy in mouse models. In vitro, second-generation CAR T cells with a CD28zeta costimulatory domain failed to expand for the first 4 days after transduction, but subsequently expanded with similar kinetics as non-transduced cells resulting in an almost 100% CAR-positive infusion product with predominate effector memory phenotype. Strikingly, CAR-positive T cells completely downregulated CD47 and potent fratricide was observed against CD47-positive non-transduced T cells in coculture. In vitro, the CD47-directed CAR T cells secreted interferon gamma and killed multiple different lines of target-positive cancer cells, however, they completely lacked antitumor efficacy in vivo and failed to persist past 1 day post-infusion. Knockout of CD47 in CAR T cells directed against a different target resulted in similar failure to persist. Macrophages phagocytosed CD47-knockout CAR T cells in vitro, and depletion of macrophages enhanced the persistence as well as efficacy of CD47 knockout CAR T cells in vivo. These findings underscore the importance of CD47 expression for T cell expansion and persistence in vivo, which must be accounted for in any future development of approaches targeting the CD47-SIRPalpha axis in the context of adoptive cell therapy.