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Tumor-Infiltrating Lymphocytes (TILs)

Tumor-Infiltrating Lymphocytes (TILs): Role in Cancer Immunity and Therapy

Tumor-infiltrating lymphocytes (TILs) are immune cells that migrate from the bloodstream into tumors, playing dual roles in tumor suppression and disease progression. Their presence and composition correlate with clinical outcomes and therapeutic responses in multiple cancers.

Composition and Detection

TILs encompass diverse immune cells:

Immune Cell Type	Function	Prognostic Relevance
CD8+ T cells	Direct tumor cell killing via cytotoxicity.	High levels → improved survival13.
CD4+ T cells	Modulate immune response (helper/regulatory).	Regulatory T cells (Tregs) → immunosuppression36.
B cells	Produce tumor-specific antibodies.	Associated with better outcomes23.
NK cells	Innate tumor cell lysis.	Enhanced anti-metastatic activity17.
Macrophages	Pro-tumor (M2) or anti-tumor (M1) polarization.	M2 dominance → poor prognosis3.

• Detection Methods:
  • Histology: CD3/CD8 staining for T cells; CD20 for B cells1.
  • Gene Expression: RNA sequencing (e.g., CIBERSORT) quantifies immune infiltration13.

Clinical Significance

1. Prognostic Biomarker:
   • Melanoma: Dense TIL infiltration predicts better survival and response to immunotherapy46.
   • Breast Cancer:
     • TNBC/HER2+: Each 10% increase in stromal TILs reduces recurrence by 15–20%23.
     • Lymphocyte-predominant BC (LPBC): TILs >50–60% → improved survival2.
   • Colorectal Cancer: High TILs correlate with reduced metastasis3.
2. Therapeutic Applications:
   • Adoptive Cell Therapy (ACT):
     • Process:
       1. Tumor resection: Harvest TILs from tumor tissue46.
       2. Ex vivo expansion: Amplify TILs 10,000-fold with IL-224.
       3. Lymphodepletion: Chemotherapy clears immunosuppressive cells46.
       4. Reinfusion: Expanded TILs + IL-2 enhance anti-tumor activity48.
     • Efficacy:
       • Melanoma: 50–70% response rates in advanced cases46.
       • Cervical/Cholangiocarcinoma: Promising early results26.
   • Combination Therapies:
     • Checkpoint inhibitors (anti-PD-1/CTLA-4) → rescue exhausted TILs36.

Challenges

1. Tumor Microenvironment (TME):
   • Immunosuppression: Tregs, PD-L1, and cytokines (e.g., TGF-β) inhibit TIL function36.
   • Heterogeneity: Variable TIL density and antigen specificity across tumors26.
2. Technical Hurdles:
   • Low TIL viability: Requires optimized expansion protocols68.
   • Cost/Time: ACT production takes 3–6 weeks46.

Future Directions

1. Biomarker-Driven Therapy:
   • Tissue-resident memory T cells (TRMs): CD8+CD69+CD103+ cells predict survival in TNBC2.
   • Neoantigen profiling: Personalize TIL selection for ACT68.
2. Engineering Enhancements:
   • Gene editing: Knockout PD-1 or enhance TCR affinity68.
   • Cytokine support: IL-15/IL-21 to sustain TIL activity post-infusion6.

Conclusion

TILs are critical mediators of anti-tumor immunity, with prognostic and therapeutic value in solid cancers. While challenges like TME suppression persist, advances in ACT and biomarker-guided strategies are expanding their clinical utility.

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References

1. TIL Composition and Detection1
2. TIL Therapy and Prognostic Role2
3. TME and TIL Dynamics3
4. TIL Therapy Process4
5. TIL Challenges and Engineering6
6. TIL Definition and Mechanisms8