Immunobiology and Immunotherapy of Kidney Cancer
Kidney cancer is diagnosed in 80,000 Americans each year and causes 14,000 deaths. It is very difficult to cure once it has spread outside the kidneys. It has long been known, however, that immune therapies – such as infusion of Interleukin-2 or treatment with immune checkpoint inhibitors – can be effective against advanced kidney cancer, particularly against renal cell carcinoma (RCC), the most common subtype of kidney cancer. The antitumor activity of immune checkpoint inhibitors against RCC is mediated by CD8+ and CD4+ T cells, but surprisingly little is known about the target antigens recognized by T cells on RCC tumor cells. One ongoing project in the Warren Lab, funded by the American Association for Cancer Research (AACR) and the Kidney Cancer Association (KCA), is investigating whether peptides derived from translation products of human endogenous retrovirus (hERV) sequences create antigens recognized by RCC-reactive T cells. HERVs make up about 8% of the human genome and are remnants of ancient retroviral infections that have integrated into the genome. It is thought that most HERV sequences are inactive, but in RCC and other types of cancer these genetic elements are often expressed, potentially creating tumor-specific targets for T cells.
Another current project, funded by the Washington Research Foundation (WRF), is exploring whether T cells genetically engineered with a lentivirus to express a chimeric antigen receptor (CAR) specific for the FOLR1 (folate receptor alpha) protein – which is overexpressed in RCC and several other types of cancer – might have activity against RCC. An antibody-drug conjugate specific for the FOLR1 protein has already been approved by the FDA for the treatment of ovarian cancer, and other FOLR1-directed therapeutics are being evaluated in clinical trials for several cancers including ovarian, breast, and non-small cell lung cancer.
Lifileucel, an autologous tumor-infiltrating lymphocyte (TIL) therapy, received accelerated FDA approval in February 2024 to treat metastatic melanoma in patients whose disease was refractory to an anti-PD-1 immune checkpoint inhibitor. The success of lifileucel has accelerated interest in the application of TIL therapy to other solid tumors. RCC tumors exhibit dense CD8+ T-cell infiltration and cytolytic gene expression, which has suggested that an analogous approach might prove effective for RCC. The Kuni Foundation is supporting a major ongoing effort in the Warren Lab to develop TIL therapy for RCC.
Quantitative Understanding of Epitope Specificity in T-cells (QUEST)
T-cells represent one of the body's most powerful defenses against cancer and viral pathogens, with over 10^9 T-cells in every individual, each bearing unique T-cell receptors capable of recognizing peptide-MHC complexes associated with disease. This remarkable diversity emerges through an intricate process of combinatorial V(D)J gene segment rearrangement, followed by random junctional insertions and deletions, creating a vast repertoire of receptors with overlapping specificities. The recognition event itself is a five-piece molecular puzzle where the alpha and beta chains of the TCR must align appropriately with an antigenic peptide nestled within the groove of two MHC chains. Rather than operating through strict lock-and-key mechanisms, these are relatively low-affinity interactions characterized by cross-reactivity—individual TCRs can recognize multiple different peptide-MHC complexes, while any given peptide-MHC can be bound by multiple different TCRs. This flexibility allows the immune system to provide broad coverage across an enormous, though finite, T-cell repertoire, yet identifying which TCRs will productively engage specific disease-associated antigens remains a needle-in-a-haystack problem critical for developing effective immunotherapies and vaccines. To address this challenge, we are leveraging the exponential growth in next-generation sequencing data and experimentally validated databases to build predictive models that can decode the principles governing these promiscuous molecular interactions. By conceptualizing TCR-peptide-MHC binding as phrases within a language governed by a yet undetermined grammar, we aim to build fine-tuned protein language models that capture the nuanced rules underlying immune recognition, thus enabling us to computationally predict the interaction between these molecules. Supporting this effort, we have assembled an unprecedented benchmark dataset encompassing over 741 million TCR beta chains, 19 million TCR alpha chains, 1 million paired TCR alpha-beta sequences, 1 million peptide-MHC interactions, and 22,000 complete TCR-peptide-MHC ternary complexes—providing the foundation for discovering the grammatical principles that govern cross-reactive immune recognition. A generalizable sequence prediction model for TCR-peptide-MHC interactions can accelerate the screening and validation of targets for therapeutic vaccines and T-cell therapies for cancer.
Comprehensive Characterization of the T-cell Response to KSHV to Enable Specific Immune Therapy
Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease. KS causes significant morbidity and mortality worldwide, particularly in people living with HIV (PLWH) and in sub-Saharan Africa (SSA) where KSHV seroprevalence is high. It is estimated that 80% of the KS burden in SSA, where the impact of KS is heaviest, is attributable to HIV infection. KS most often develops in the setting of T-cell deficiency or dysfunction, such as in KSHV-seropositive individuals with HIV infection or KSHV-seropositive recipients of solid organ or allogeneic hematopoietic cell transplants. In these settings KS can remit following initiation of antiretroviral therapy (ART) or withdrawal of immune suppression. In SSA, primary infection with KSHV is thought to occur in childhood, but most cases of KS and other KSHV-associated disease in both PLWH and people without HIV infection develop many years, often several decades, later. These observations suggest that loss or impairment of a T-cell component of pre-existing KSHV-specific immunity underlie the development of these diseases. Strategies that preserve or restore the T-cell component of KSHV-specific immunity in PLWH and others at risk should, therefore, have potential for the prevention or treatment of KSHV-associated disease.
Our previous studies of tumor biopsies and blood samples from people in Uganda living with HIV and KS as well as adults with KS but no concurrent HIV infection have identified a large repertoire of T-cells that are likely to be specific for KSHV. We are identifying the antigenic targets of these putative KSHV-specific T-cells and find that they demonstrate high avidity for KSHV-encoded peptides, recognize KSHV-infected cells, are detectable in KS tumors, circulate in blood, and persist across time. We believe that immune interventions that preserve, enhance, or restore the T-cell response to KSHV will prove effective for the prevention or treatment of KS, particularly in PLWH who are at greatest risk. Comprehensive definition of the targets of the KSHV-specific T-cell response in KSHV-seropositive individuals and of how that T-cell response is impaired or disabled in individuals who develop KS will provide the blueprint for such immune interventions. Current studies in our lab are laying the foundation for specific immune therapy for KS by identifying the major targets of the T-cell response to KSHV, identifying those that are naturally presented by KSHV-infected cells, and defining mechanisms by which KSHV attempts to evade that response.