The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Wang, C. et al. Nature Cancer. 6: 801–819. (2025).
doi: 10.1038/s43018-025-00946-x.
Summary of the findings
Using serial blood and tumor samples collected before and after TIL infusion in lung cancer patients, we combined antigen reactivity assays with multi-omic sequencing to match targeted tumor antigens to specific T cell clonotypes. Most tumor-reactive clonotypes were CD4+ T cells that persisted longer than the other infused clonotypes. Furthermore, higher numbers of infused tumor-reactive TILs correlated with clinical benefit, which we defined as survival beyond six months without additional systemic therapy. Resistance arose when reactive TILs became exhausted or when tumors lost antigen expression, especially subclonal neoantigens. Resistance also arose from mutation of the presenting HLA type, undermining epitope presentation. Unexpectedly, classic tissue-resident memory markers (ITGAE, ZNF683) and CD39−CD69− stem-like TILs did not predict response, suggesting infused TILs operate under different rules than resident intra-tumoral T cells.
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Future impact
These results underscore TIL therapy’s areas for future improvement. Tumors can swiftly adapt by shedding the antigens targeted by infused T cell clones, mirroring CAR T challenges where target loss or dwindling memory-like cells drive relapse. Although TILs’ multi-specificity offers an advantage, it may need to be paired with other technology, such as a CAR-T to circumvent HLA loss. The logistical demands of TIL therapy add another barrier. It requires surgery and weeks of ex vivo expansion, during which cells may lose potency. Efficacy depends on unknown factors such as TIL reactivity, in vivo persistence, antigen retention, and matching HLA alleles. To overcome resistance, future strategies will focus on immune engineering to enhance TIL survival and on designing T cells against clonal neoantigens, a promising but currently limited approach, due to the need for identified T cell receptors. Multiplex methods to identify T cell receptors against public neoantigens may be other technology to pair with polyclonal TIL for the future.
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