JITC Editor Picks
Hongfei Wang, Yixuan Sun, Xiuman Zhou, Chunxia Chen, Ling Jiao, Wanqiong Li, Shanshan Gou, Yanying Li, Jiangfeng Du, Guanyu Chen, Wenjie Zhai, Yahong Wu, Yuanming Qi, Yanfeng Gao
Journal for ImmunoTherapy of Cancer 2020;8:e000905 (5 October 2020)
Tumor cells express the ‘don't eat me’ signal CD47 on their surfaces, which suppresses phagocytosis by macrophages through interaction with SIRPalpha. Previous efforts at targeting CD47 with monoclonal antibodies have been associated with profound anemia, as the receptor is also found on hematopoietic stem and progenitor cells. Reasoning that a small peptide-based therapeutic could sidestep some systemic toxicity and enhance tumor penetration, Hongfei Wang et al performed five rounds of phage-display biopanning to identify a short fragment that specifically bound CD47 and blocked interaction with SIRPalpha. The lead candidate as validated by in vitro binding assays, pep-20, was shown to enhance macrophage-mediated phagocytosis of three different human tumor cell lines (MCF7, HT29 and Jurkat) in culture. In two mouse models of colon cancer (MC38 and CT26), peritumoral pep-20 subcutaneous injection slowed tumor growth and prolonged survival with no significant toxicity. Notably, intratumoral CD8+ T cell populations, as well as interferon gamma expressing CD8+ T cells were significantly increased in tumor-draining lymph nodes and spleen after treatment with pep-20. Depletion of macrophages eliminated anti-tumor activity of pep-20. A docking model was generated in silico, which led to the development of a D-amino acid-subsituted isomer, pep-20-D12. Unlike the parent peptide, which only showed anti-tumor activity with local administration, pep-20-D12 demonstrated significant slowing of tumor progression when administered systemically. Notably, when given in combination with radiotherapy, pep-20-D12 led to significant delay and sometimes complete regression of tumor growth. Most surprisingly, perhaps, phagocytosis of malignant cells was demonstrated by tumor infiltrating monocytic myeloid-derived suppressor cells after radiotherapy with pep-20-D12. The peptide may be a promising candidate for further development, emphasizing the future potential for targeting the myeloid compartment for immunotherapy.
Alissa Keegan, Biagio Ricciuti, Padric Garden, Limor Cohen, Reiko Nishihara, Anika Adeni, Cloud Paweletz, Julianna Supplee, Pasi A Jänne, Mariano Severgnini, Mark M Awad, David R Walt
Journal for ImmunoTherapy of Cancer 2020;8:e000678 (5 October 2020)
No blood-based biomarkers reliably predict efficacy of immune checkpoint blockade for solid tumors. Hypothesizing that changes in systemic cytokine levels with initial doses of anti-PD-(L)1 therapy may correlate with clinical responses, Alissa Keegan and colleagues took advantage of new ultrasensitive single-molecule array (Simoa) technology to measure protein levels down to attomolar concentrations, in two cohorts of patients with non-small cell lung cancer that received anti-PD-(L)1 immunotherapy. In the first cohort of 47 patients (33 treated with pembrolizumab, 10 with nivolumab, and 4 with other agents), a decrease of serum IL-6 levels of 40% or more on treatment was associated with longer progression-free survival (PFS). On-treatment IL-6 levels ranged from 0.60 to 78? pg/mL, and the quartile with the lowest levels tended to have longer PFS. In more detail, the 11 patients with reduced IL-6 after checkpoint blockade had a median PFS of 11 months (95%? CI 4.2 to not reached), whereas those with stable (n=21) or increased IL-6 (n=15) had median PFS of 5 months (95%? CI 3.4 to not reached) and 4 months (95%? CI 2.3 to not reached), respectively. Although IL-6 change did not retain a significant association with PFS in a multivariate model after adjusting for age, performance status, PD-L1 and TMB, the sample size was small and, neither did the known prognostic factors PD-L1 and TMB. In a second cohort where 10 additional ultrasensitive Simoa plasma cytokine assays were performed, IL-6 percentage decrease was not statistically associated with PFS with immunotherapy (n=25) or chemoimmunotherapy (n=16), although a trend toward significance was observed. A significant association between IL-6 levels and C-reactive protein levels was seen in this second cohort. None of five other known inflammatory cytokines (IL-10, CXCL10, IL-17A, IL-15, and IL-1-beta) demonstrated statistically significant association with clinical responses. This study lays the groundwork for further development of blood-cytokine level-based biomarkers for response to checkpoint blockade, pending validation in larger cohorts with greater statistical power as well as in additional disease settings.
Hannah S Newton, Vaibhavkumar S Gawali, Ameet A Chimote, Maria A Lehn, Sarah M Palackdharry, Benjamin H Hinrichs, Roman Jandarov, David Hildeman, Edith M Janssen, Trisha M Wise-Draper, Laura Conforti
Journal for ImmunoTherapy of Cancer 2020;8:e000844 (14 October 2020)
Ion channels are integral to almost all aspects of cytotoxic T cell anti-tumor functions including migration, proliferation, and cytokine production. Hypothesizing that ion channels may also play a role in mechanisms of resistance to immunotherapies targeting the PD-(L)1 axis, Hannah S Newton et al performed a series of sophisticated electrophysiology experiments on tumor-infiltrating lymphocytes (TILs) isolated from samples from immunotherapy-experienced and immunotherapy-naïve cohorts of patients with squamous cell carcinoma of the head and neck (HNSCC). Of the two voltage-gated ion channels that are critical for T cell effector function, pembrolizumab treatment was not associated with any difference in TIL KCa3.1 activity; however, Kv1.3 activity in CD8+ TILs was higher in samples from patients who were treated with pembrolizumab—independent of expression levels—and the increase in Kv1.3 activity was more pronounced for responsive disease (72% versus 180%). In circulating T cells, pembrolizumab treatment was associated with immediate initial increases in KCa3.1 activity for all patients. Patients with responsive disease, however, showed a sustained increase of Kv1.3 activity. Long-lasting increases in calcium fluxing were also observed in peripheral blood T cells from patients with responsive disease after pembrolizumab treatment, which accompanied increased interferon gamma production in this cohort. Intriguingly, while T cells from patients with pembrolizumab-non-responsive disease showed significant mobility defects in the presence of adensosine, chemotaxis was not inhibited by adenosine for peripheral blood T cells from patients with pembrolizumab-responsive disease—similar to what was seen with cells from healthy donors. The findings for the first time reveal a critical contribution of ion channels in response to checkpoint blockade.
Sarah Nicol Lauder, Kathryn Smart, Veerle Kersemans, Danny Allen, Jake Scott, Ana Pires, Stefan Milutinovic, Michelle Somerville, Sean Smart, Paul Kinchesh, Elena Lopez-Guadamillas, Ellyn Hughes, Emma Jones, Martin Scurr, Andrew Godkin, Lori S Friedman, Bart Vanhaesebroeck, Awen Gallimore
Journal for ImmunoTherapy of Cancer 2020;8:e000693 (22 October 2020)
PI3Kdelta inhibition is already used in the treatment of hematologic malignancies, and recent studies demonstrate that targeting PI3Kdelta may further promote antitumor immunity for solid cancers by dampening regulatory T cells (Tregs). Sarah Nicol Lauder and colleagues thoroughly characterize the mechanisms by which PI3Kdelta inhibition may enhance antitumor immunity, through effects on both effector T cells and Tregs, and further demonstrate potential synergy with LAG3 inhibition for enhanced cancer control. In mouse models of triple negative breast cancer (4T1 tumors), PI3Kdelta inhibitor monotherapy leads to attenuated tumor growth rates in all treated animals, but regression of malignant masses was only seen in roughly 12.5% of animals. Phenotypic analysis of effector T cells from regressing tumors after PI3Kdelta inhibition showed significant expansions of gp70 antigen-reactive CD8+ tumor infilitrating lymphocytes (TILs), increased TCF1+ CD4+ TILs, and a relative lack of expression of CD69 on CD8+ TILs compared to in non-regressing tumors. Furthermore, Glut1 expression was clearly higher on CD8+ T cells isolated from regressor tumors after PI3Kdelta inhibition, as was mitochondrial membrane potential in tumor-infiltrating CD4+ and CD8+ T cells compared with control mice. In non-regressing tumors after PI3Kdelta inhibition, the proportion of Tregs expressing LAG3 as well as CD69 were both higher, and proliferation, measured by Ki67 staining, was enhanced compared to in regressing tumors. Treatment with anti-CD69 blocking antibodies, either alone or in combination with PI3Kdelta inhibition had no effect on tumor growth. However, anti-LAG3 in combination with PI3Kdelta inhibition resulted in significantly greater tumor control than either monotherapy, leading to regression in 50% of the mice treated with the dual regimen. Studies in MC38 and CT26 colon cancer cell lines showed similar synergy. The results support further study of PI3Kdelta inhibition combined with LAG3 as a strategy to enhance efficacy for checkpoint blockade beyond the PD-(L)1 axis.
Maria Zagorulya, Ellen Duong, Stefani Spranger
Journal for ImmunoTherapy of Cancer 2020;8:e001204 (5 October 2020)
Checkpoint blockade therapy achieves exceptional results against some malignant melanomas, lung, and kidney carcinomas, yet the fraction of patients who derive benefit from these therapies for several other malignancies, including pancreatic cancer and ovarian cancer is disappointingly low. Additionally, metastatic lesions to the liver respond very poorly to checkpoint blockade. Because myeloid cells are known to shape anti-tumor T cell responses, Maria Zagorulya, Ellen Duong and Stefani Spranger review the tissue-resident myeloid antigen-presenting cells (APCs) in different tumor types, with an emphasis on the contribution of dendritic cells (DCs) to disease control. Adding nuance to the traditional view of the cancer-immunity cycle, in which myeloid APCs provide the key initiating stimulus to initiate anti-tumor T cell responses, the review provides evidence that prevalence and characteristics of distinct DC subsets within the tumor microenvironment—especially conventional type 1 DCs (cDC1s)—varies substantially between checkpoint blockade-responsive and non-responsive tumors. The review establishes a framework to consider myeloid-targeted modulatory strategies to stimulate DCs residing at different organ sites.