Mechanism of action of BCG-tumor cell vaccines in the generation of systemic tumor immunity. II. Influence of the local inflammatory response on immune reactivity.

The intradermal injection of a vaccine composed of 10(7) X-irradiated syngeneic hepatocarcinoma line 10 (L10) cells admixed with 10(8) Mycobacterium bovis strain BCG into inbred Sewall Wright strain 2 guinea pigs induces a local inflammatory reaction and effectively immunizes against a contralateral challenge with viable L10 cells. The relationship between the local inflammatory reaction and the generation of tumor immunity was studied. Immunization against L10 was most effective when both L10 cells and BCG were injected into the same site, less effective when they were injected into separate sites with common lymphatic drainage, and not effective when they were injected at totally separate sites. Enzymatic dissociation of dermal vaccination sites revealed that vaccination with BCG and L10 cells combined induced a significantly greater inflammatory response than did vaccination with BCG alone or L10 cells alone; the inflammatory response was also greater than the combination of these individual responses, suggesting that BCG and L10 cells interacted synergistically in the elicitation of an inflammatory response. Sites receiving a combined vaccine of BCG and L10 cells were infiltrated rapidly by inflammatory cells, and surgical excision of these sites as early as 24 hours after vaccine administration did not affect significantly the development of immune responsiveness. However, vaccination sites induced by the injection of BCG and L10 cells at separate but adjacent sites were slowly infiltrated by inflammatory cells, and surgical removal of these sites within 96 hours of vaccination inhibited later immune responsiveness. Quantitative cellular analysis of these inflammatory reactions showed that inflammation was related to tumor-reactive immunity such that the greater the initial inflammatory process, the greater the resistance to tumor challenge.