CD19 structure, expression, and signaling: From basic mechanisms to therapeutic targeting.

The role of CD30 in atopic disease.

CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting.

SYK Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia

Bispecific antibodies can activate T cells that target tumor cells expressing mutant RAS and p53 neoantigens (Bridging the Gap by Mike via Flickr)Developing therapeutics that target the mutant RAS and p53 proteins that drive many tumors has proven challenging. Hsiue et al. and Douglass et al. report the development of bispecific antibodies that target mutant p53 and RAS, respectively. After using mass spectrometry to identify a p53 neoantigen, Hsiue et al. screened a phage library to select an scFV specific for the neoantigen–HLA complex. This scFV was used to generate a bispecific antibody that induces T cells to kill tumor cells in a neoantigen-specific manner. Using the same approach, Douglass et al. were able to generate a bispecific antibody that induces T-cell killing of tumor cells expressing mutant RAS. Future studies will investigate whether such bispecific antibodies have therapeutic potential.Hsiue EH-C, …, Zhou S. Science 2021 Mar 5;371:eabc8697.Douglass J, …, Zhou S. Sci Immunol 2021 Mar 1;6:eabd5515.Healthy human T cell (from National Institute of Allergy and Infectious Diseases via Flickr)Consistent with previous studies testing CAR-T cells as a treatment for solid tumors, Srivastava et al. find that in patients with breast or lung cancer expressing receptor tyrosine kinase-like orphan receptor 1 (ROR1) who receive cyclophosphamide/fludarabine pretreatment for lymphodepletion, ROR1 CAR-T cells infiltrate tumors poorly and become dysfunctional rapidly. In mice, adding oxaliplatin to cyclophosphamide for lymphodepletion induces tumor macrophage production of T cell–recruiting chemokines, enhancing tumor infiltration by ROR1 CAR-T cells. These data are clinically relevant, as lymphodepletion with oxaliplatin/cyclophosphamide is shown to improve tumor infiltration by ROR CAR-T cells in a patient with ROR+ breast cancer.Srivastava S, …, Riddell S. Cancer Cell 2021 Feb 8;39:193–208.e10.Killer T cells surround a cancer cell (by Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths via NCI Visuals Online)Characterizing tumor-specific T cells in the blood has great therapeutic value. Pauken et al. perform single-cell RNA and TCR sequencing of CD8+ T cells in paired blood and tumor samples and identify NKG2D, CD39, and CXCR1 as candidate markers for tumor-specific CD8+ T cells. Lucca et al. perform similar experiments in melanoma patients and show that circulating T cells exhibit similar effector gene signatures as TCR-matched tumor-infiltrating T cells but do not have exhaustion gene signatures. These results help identify selective markers for tumor-specific CD8+ T cells in the blood.Pauken KE, …, Singer M. J Exp Med 2021 Mar 2;218:e20200920.Lucca LE, …, Hafler DA. J Exp Med 2021 Mar 2;218:e20200921.Lactic acid metabolism promotes Tregs (from Fig. 1 of de la Cruz-Lopez, Front Immunol 2019)Immune cell metabolism can impact the efficacy of cancer immunotherapy. Watson et al. show that regulatory T cells (Treg) are metabolically flexible. Treg function and stability are impaired by high-glucose conditions, but Tregs can upregulate pathways involved in lactic acid metabolism, and this maintains their suppressive phenotype in the tumor microenvironment (TME). Zappasodi et al. find that anti–CTLA-4 promotes destabilization of Tregs in the TME. This is dependent on glycolysis and CD28 signaling and results in Tregs gaining a more effector phenotype in tumors lacking LDHA (lactic acid dehydrogenase A). These two articles shed light on the complexity of metabolic regulation occurring in the TME.Watson MJ, …, Delgoffe GM. Nature 2021 Feb 15. DOI: 10.1038/s41586-020-03045-2.Zappasodi R, …, Merghoub T. Nature 2021 Feb 15. DOI: 10.1038/s41586-021-03326-4.Breast tumor microenvironment (by Joseph Szulczewski, David Inman, Kevin Eliceiri, and Patricia Keely via NCI Visuals Online)The landscape of tumor-infiltrating myeloid cells (TIM) among different tumor types remains poorly understood. Cheng et al. perform pan-cancer single-cell transcriptional analysis of TIMs from 210 patients across 15 cancer types. Highlights of the data include: The ratio of TNF+ to VEGFA+ mast cells is associated with prognosis in nasopharyngeal cancer; cDC1-derived LAMP3+ cDCs express higher IL12B and BTLA, whereas cDC2-derived LAMP3+ cDCs show higher expression of CD1E and CCL17; and proangiogenic tumor-associated macrophages have distinct markers in different cancer types. Together, these results point to the heterogeneity of TIMs and new approaches to therapeutic targeting of TIMs.Cheng S, …, Zhang Z. Cell 2021 Feb 4;184:792–809.e23.The gut microbiota can impact immunotherapy (by DataBase Center for Life Science via Wikimedia Commons)The gut microbiome composition correlates with efficacy of immune checkpoint blockade, but whether this can be leveraged to overcome therapy resistance is not clear. Two clinical studies by Davar et al. and Baruch et al. address this and show that fecal microbiota transplantation in combination with anti–PD-1 is safe and efficacious in patients with anti–PD-1 refractory melanoma. Some patients had complete or partial responses, and responders had distinct expression, proteomic, and metabolic signatures, as well as alteration of the microbiota composition. The data from these two clinical studies highlight a novel treatment option to overcome anti–PD-1 resistance in melanoma.Davar D, …, Zarour HM. Science 2021 Feb 5;371:595–602.Baruch EN, …, Boursi B. Science 2021 Feb 5;371:602–9.

CD19-CAR Cytokine Induced Killer Cells Armored with IL-18 Control Tumor Burden, Prolong Mouse Survival and Result in In Vivo Persistence of CAR-CIK Cells in a Model of B-Cell Acute Lymphoblastic Leukemia

Costimulation was originally defined and characterized during primary T cell activation. The signaling events that regulate subsequent antigen encounters by T cells are less well defined. In this study we examined the role of CD30 in T cell activation and defined factors that regulate expression of CD30 on T cells. We demonstrate that CD30 expression is restricted to activated T cells and regulated by CD28 signal transduction. In contrast to CD28-expressing TCR Tg cells, CD28-deficient TCR Tg cells did not express CD30 when cultured with peptide and APCs. However, rIL-4 reconstituted CD30 expression on CD28-deficient TCR Tg cells. Blockade of CD28 interactions or depletion of IL-4 inhibited the induction of CD30, suggesting that both CD28 and IL-4 play important roles in the induction of CD30 expression on wild-type cells. However, CD28 signaling did not up-regulate CD30 expression solely through its ability to augment IL-4 production because IL-4-deficient T cells stimulated with anti-CD3 and anti-CD28 expressed CD30. Induction of CD30 in the absence of IL-4 was not due to the IL-4-related cytokine IL-13. CD30, when expressed on an activated T cell, can act as a signal transducing receptor that enhances the proliferation of T cells responding to CD3 crosslinking. Collectively, the data suggest that T cell expression of CD30 is dependent on the presence of CD28 costimulatory signals or exogenous IL-4 during primary T cell activation. Once expressed on the cell surface, CD30 can serve as a positive regulator of mature T cell function.

Adult T‐cell leukemia/lymphoma (ATL) develops via stepwise accumulation of gene mutations and chromosome aberrations. However, the molecular mechanisms underlying this tumorigenic process are poorly understood. We previously reported the presence of a biological link between the expression of CD30, which serves as a marker for ATL progression, and the actively proliferating fraction of human T‐cell leukemia virus type 1 (HTLV‐1)‐infected cells that display polylobulation. Here, we demonstrated that CD30 signaling induced chromosomal instability with clonal expansion through DNA double‐strand breaks (DSBs) via an increase of intracellular reactive oxygen species. CD30+ATL cells were composed of subclones with additional genomic aberrations compared with CD30−ATL cells in ATL patients. Furthermore, we found an accumulation of copy number loss of DSB repair‐related genes as the disease progressed. Taken together, CD30 expression on ATL cells appears to be correlated with genomic instability, suggesting that CD30 signaling is one of the oncogenic factors of ATL progression with clonal evolution. This study provides new insight into the biological roles of CD30 signaling and could improve our understanding of tumorigenic processes of HTLV‐1‐infected cells.

Chronic CD30 signaling in B cells results in lymphomagenesis by driving the expansion of plasmablasts and B1 cells

CD4 and CD30 Coexpression in a Cutaneous Manifestation of Systemic Mastocytosis-A Pitfall.

CD30, a member of the tumor necrosis factor receptor superfamily, plays roles in pro-survival signal induction and cell proliferation in peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). Previous studies have identified the functional roles of CD30 in CD30-expressing malignant lymphomas, not only PTCL and ATL, but also Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and a portion of diffuse large B-cell lymphoma (DLBCL). CD30 expression is often observed in virus-infected cells such as human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is capable of immortalizing lymphocytes and producing malignancy. Some ATL cases caused by HTLV-1 infection overexpress CD30. However, the molecular mechanism-based relationship between CD30 expression and HTLV-1 infection or ATL progression is unclear. Recent findings have revealed super-enhancer-mediated overexpression at the CD30 locus, CD30 signaling via trogocytosis, and CD30 signaling-induced lymphomagenesis in vivo. Successful anti-CD30 antibody-drug conjugate (ADC) therapy for HL, ALCL, and PTCL supports the biological significance of CD30 in these lymphomas. In this review, we discuss the roles of CD30 overexpression and its functions during ATL progression.

OP0141 #X00A0; CD28 AS A POTENTIAL THERAPEUTIC TARGET FOR GIANT CELL ARTERITIS

A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory B-Cell Malignancies

CD28-Mediated Pro-Survival Signaling in Multiple Myeloma

CD28 Signaling Controls Metabolic Fitness of Pathogenic T Cells in Medium and Large Vessel Vasculitis

Prevalence and Clinical Characterization of CD20 and CD22 Expression in Pediatric Precursor B-Cell Acute Lymphoblastic Leukemia