Costimulatory and -inhibitory molecules on tumor-infiltrating lymphocytes from colorectal carcinoma and its metastases

Colorectal carcinoma (CRC) is the most common malignancy, and is a cause of
substantial morbidity and mortality. Curative treatment is possible, but
strongly depends on the stage of the disease. Surgical resection, possibly
supported by chemotherapy, is applied when the disease is contained in colon
or rectum (stage I, II) or has metastasized to the lymph nodes (stage III).
When the tumor has metastasized to other tissues (mostly lung or liver; stage
IV), chemotherapy and monoclonal antibodies are applied, sometimes combined
with surgical resection. Treatment of metastasized disease has only limited
life-extending effect, with less than 5% five year survival of patients.
Immunotherapy represents an attractive alternative treatment option, because it
is highly specific and can induce long-lasting immunological memory that may
permanently prevent tumor recurrence. It is our ultimate goal to design
effective immunotherapy for CRC patients. In the present study we aim to
identify targets for immunotherapy by focusing on the tumor-infiltrating
lymphocytes.
We hypothesize that costimulatory or co-inhibitory molecules on the surface of
lymphocytes can be targeted to affect lymphocyte function as an
immunotherapeutic strategy to combat CRC.

To determine which costimulatory and co-inhibitory molecules are expressed on
tumor-infiltrating lymphocytes (TIL) derived from patients with CRC (including
metastasized CRC), and to study the effects of targeting these molecules on
their function in ex vivo assays.

Cohort study in CRC patients in our centers that are undergoing resection of
CRC or other tissue to which CRC has metastasized. Tumor-infiltrating
lymphocytes will be isolated from residual tumor tissue and adjacent tumor-free
tissue not needed for histological evaluation (*restmateriaal*). Their
phenotype will be evaluated by flow cytometry and their function, including
effects of targeting costimulatory and co-inhibitory surface molecules, in cell
culture experiments. Blood is needed for comparison and to provide sufficient
antigen presenting cells for in vitro T cell assays. In addition, leukocytes
and plasma will be stored in a biobank for future studies.

Intervention: invasive measurement of 80 mL of blood collected during surgery.
No benefit and negligible risk for the patients. Blood is taking once during
surgery and so no additional intervention is needed. Hopefully, the results of
the study will benefit CRC patients in the near future.