Biology subjects

Kandalaft, L. E.

Publications and source records attributed to Kandalaft, L. E..

3 recordsLinked to original sources

bioRxiv2023

Tumor-reactive clonotype dynamics underlying clinical response to TIL therapy in melanoma

The profiles, specificity and dynamics of tumor-specific clonotypes that are associated with clinical response to adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) remain unclear. Using single-cell RNA/TCR-sequencing, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients treated with TIL-ACT. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, which were more effectively mobilized upon in vitro expansion, yielding products with higher numbers of tumor-specific CD8+ cells, which also preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes, and with cell products mostly composed of blood-borne clonotypes mainly persisting in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost the specific signatures of states originally exhibited in tumors, including exhaustion, and in responders acquired an intermediate exhausted effector state after tumor engraftment, revealing important functional cell reinvigoration.

cancer biology↗

bioRxiv2022

Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma

Adoptive cell therapy (ACT) using ex vivo expanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+ TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+ T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials. One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+ TIL-myeloid cell networks

immunology↗

bioRxiv2017

Deciphering HLA motifs across HLA peptidomes correctly predicts neo-antigens and identifies allostery in HLA specificity

The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal allosteric modulation of the binding specificity of HLA-I alleles and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

bioinformatics↗