The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical/Translation co-Section Editor Dr. Douglas McNeel.
“Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance” by Dhivya Sridaran et al
Nat Commun. (2022)
Abstract:
Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.
Why this matters: The authors identify an inhibitor of ACK1 which plays a role in immune checkpoint blockade resistance, suggesting this agent might be used alone or in combination with other agents to treat cancers currently unresponsive to immune checkpoint blockade.
“Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression” by Sean H. Colligan et al
J Clin Invest. (2022)
Abstract:
While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.
Why this matters: The article by Colligan et al is of interest as they are exploring the differentiation of myeloid-derived suppressor cells to identify agents able to differentiate these cells as a complement to tumor immunotherapy.
“Treg-Dominant Tumor Microenvironment Is Responsible for Hyperprogressive Disease after PD-1 Blockade Therapy” by Hiroaki Wakiyama et al
Cancer Immunol Res. (2022)
Abstract:
Programmed cell death 1 (PD-1) blockade therapy can result in dramatic responses in some patients with cancer. However, about 15% of patients receiving PD-1 blockade therapy experi- ence rapid tumor progression, a phenomenon termed “hyper- progressive disease” (HPD). The mechanism(s) underlying HPD has been difficult to uncover because HPD is challenging to reproduce in animal models. Near-infrared photoimmunother- apy (NIR-PIT) is a method by which specific cells in the tumor microenvironment (TME) can be selectively depleted without disturbing other cells in the TME. In this study, we partially depleted CD8þ T cells with NIR-PIT by targeting the CD8b antigen thereby temporarily changing the balance of T-cell subsets in two different syngeneic tumor models. PD-1 blockade in these models led to rapid tumor progression compared with controls. CD3eþCD8aþ/CD3eþCD4þFoxP3þ (Teff/Treg) ratios in the PD-1 and NIR-PIT groups were lower than in controls. Moreover, in a bilateral tumor model, low-dose CD8b-targeted NIR-PIT with anti–PD-1 blockade showed rapid tumor progres- sion only in the tumor exposed to NIR light. In this experiment CD8b-targeted NIR-PIT in the exposed tumor reduced local CD8þ T cells resulting in a regulatory T-cell (Treg)–dominant TME. In conclusion, this reports an animal model to simulate the Treg-dominant TME, and the data generated using the model suggest that HPD after PD-1 blockade therapy can be attributed, at least in part, to imbalances between effector T cells and Tregs in the TME.
Why this matters: The article suggests that tumor-infiltrating Treg can markedly negatively influence the response to PD-1 blockade therapies.
“Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade” by Hayden Pearce et al
Cancer Immunol Res. (2023)
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4þ T cells expressed a CCR6þCD161þ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8þ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103þCD39þ T cells was also observed within the CD8þ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1þTIGITþ CD8þ T cells. Combinatorial anti–PD-1 and TIGIT blockade enhanced IFNg secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1þTIGITþ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.
Why this matters: The authors explored the expression of checkpoint molecules on tissue-resident memory CD8 T cells within pancreatic tumors, finding that these cells largely co-express PD-1 and TIGIT, providing a new rationale for this specific combination of immune checkpoint blockade.